The DOI matches its Crossref record; 77 of the 77 references it cites were found in a registry or an index; none of the 115 sources its claims cite is checked for support yet.
T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment
Open accessAbstract
Human tumors progress despite the presence of tumor associated antigen (TAA)-specific T cells. Many different molecular and cellular mechanisms contribute to the failure of T cells to eradicate the tumor. These include immune suppressive networks that impair ongoing T cell function and enable tumor escape. Recent studies have started to reveal the nature of effector T cells in the tumor microenvironment. In this article we discuss T cell anergy, exhaustion, senescence, and stemness, and review the phenotype of dysfunctional T cell subsets and the underlying molecular mechanisms in the tumor microenvironments. We suggest that targeting T cell dysfunctional mechanisms and introducing/promoting T cell stemness are important approaches to treat patients with cancer.
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In the paper
“There is evidence indicating antigen specific, T cell-intrinsic dysfunction in the tumor microenvironment [15,16].”
§ T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment > T cell anergy
What the sources say
- Not checked yetcites [15] Nazareth MR Broderick L Simpson-Abelson MR Kelleher RJ Jr Yokota SJ Bankert RB Characterization of human lung tumor-associated fibroblasts and their ability to modulate the activation of tumor-associated T cells J Immunol 2007 178 5552 5562 17442937 source
- Not checked yetcites [16] Broderick L Brooks SP Takita H Baer AN Bernstein JM Bankert RB IL-12 reverses anergy to T cell receptor triggering in human lung tumor-associated memory T cells Clin Immunol 2006 118 159 169 16271513 source
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In the paper
“This indicates a poor co-stimulatory, high co-inhibitory and therefore anergy-promoting environment.”
§ T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment > T cell anergy
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In the paper
“T cell exhaustion may be a layered or progressive process to which T cells fall upon repeated activation.”
§ T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment > T cell exhaustion
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In the paper
“T cells acquiring multiple inhibitory surface molecules in persistent disease settings such as chronic infection [37,38] and malignancies [30,**39,40], which effectively prevent T cell activation.”
§ T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment > T cell exhaustion
What the sources say
- Not checked yetcites [37] Wherry EJ Ha SJ Kaech SM Haining WN Sarkar S Kalia V Subramaniam S Blattman JN Barber DL Ahmed R Molecular signature of CD8+ T cell exhaustion during chronic viral infection Immunity 2007 27 670 684 17950003 source
- Not checked yetcites [38] Blackburn SD Shin H Haining WN Zou T Workman CJ Polley A Betts MR Freeman GJ Vignali DA Wherry EJ Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection Nat Immunol 2009 10 29 37 19043418 PMC2605166 source
- Not checked yetcites [30,**39,40]
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In the paper
“In summary, tumor induced T cell anergy may be one of the immune evasion mechanisms in patients with cancer.”
§ T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment > T cell anergy
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In the paper
“Therefore, T cell anergy may be a functional mechanism in patients with cancer.”
§ T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment > T cell anergy
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In the paper
“Given that members of the inhibitory B7 family are widely expressed by malignant cells and APCs within the human tumor microenvironment [7]”
§ T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment > T cell exhaustion
What the sources say
- Not checked yetcites [7] Zou W Chen L Inhibitory B7-family molecules in the tumour microenvironment Nat Rev Immunol 2008 8 467 477 18500231 source
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In the paper
“It is generally accepted that T cells that are presented antigen along with suboptimal CD28 co-stimulation [4,5] and/or high co-inhibition [17] result in anergic phenotypes, as characterized by their low IL-2 production and cell cycle arrest at the G1/S phase.”
§ T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment > T cell anergy
What the sources say
- Not checked yetcites [4] Schwartz RH A cell culture model for T lymphocyte clonal anergy Science 1990 248 1349 1356 2113314 source
- Not checked yetcites [5] Schwartz RH T cell anergy Annu Rev Immunol 2003 21 305 334 12471050 source
- Not checked yetcites [17] Greenwald RJ Boussiotis VA Lorsbach RB Abbas AK Sharpe AH CTLA-4 regulates induction of anergy in vivo Immunity 2001 14 145 155 11239447 source
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In the paper
“Exhausted CD8+ T cells were found in patients with melanoma [*31], ovarian cancer [9] and hepatocellular carcinoma (HCC) [30].”
§ T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment > T cell exhaustion
What the sources say
- Not checked yetcites [*31]
- Not checked yetcites [9] source
- Not checked yetcites [30] Wu K Kryczek I Chen L Zou W Welling TH Kupffer cell suppression of CD8+ T cells in human hepatocellular carcinoma is mediated by B7-H1/programmed death-1 interactions Cancer Res 2009 69 8067 8075 19826049 PMC4397483 source
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In the paper
“it is suggested that recruitment of SH2-domain containing protein tyrosine phosphatases (SHP-1 and/or SHP-2) to the immunoreceptor tyrosine-based switch motif (ITSM) within the PD-1 cytoplasmic tail inhibits signaling events, particularly PI3K/AKT activation, downstream signals of the T-cell receptor [34], and in turn results in T cell dysfunction.”
§ T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment > T cell exhaustion
What the sources say
- Not checked yetcites [34] Riley JL PD-1 signaling in primary T cells Immunol Rev 2009 229 114 125 19426218 PMC3424066 source
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In the paper
“Epigenetic factors such as IKAROS (through acetylation) [25] and Sirt1 are involved in histone modifications that promote T cell anergy [26,27].”
§ T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment > T cell anergy
What the sources say
- Not checked yetcites [25] Thomas RM Chunder N Chen C Umetsu SE Winandy S Wells AD Ikaros enforces the costimulatory requirement for IL2 gene expression and is required for anergy induction in CD4+ T lymphocytes J Immunol 2007 179 7305 7315 18025173 source
- Not checked yetcites [26] Gao B Kong Q Kemp K Zhao YS Fang D Analysis of sirtuin 1 expression reveals a molecular explanation of IL-2-mediated reversal of T-cell tolerance Proc Natl Acad Sci U S A 2012 109 899 904 22219356 PMC3271862 source
- Not checked yetcites [27] Bandyopadhyay S Dure M Paroder M Soto-Nieves N Puga I Macian F Interleukin 2 gene transcription is regulated by Ikaros-induced changes in histone acetylation in anergic T cells Blood 2007 109 2878 2886 17148585 PMC1852212 source
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In the paper
“Thus, anergy is the combined result of factors that negatively regulate proximal TCR-coupled signal transduction, together with a program of active transcriptional silencing that is reinforced through epigenetic mechanisms [6].”
§ T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment > T cell anergy
What the sources say
- Not checked yetcites [6] Wells AD New insights into the molecular basis of T cell anergy: anergy factors, avoidance sensors, and epigenetic imprinting J Immunol 2009 182 7331 7341 19494254 source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“There is an active imbalance between stimulatory and inhibitory B7 family members in the tumor microenvironment [1,3,7,8].”
- Also stated in: § T cell anergy · plain
“Human tumors and tumor associated antigen presenting cells (APCs) often express high levels of B7-H1 (CD274 or PD-L1), B7-H2 (CD275 or ICOS-L), B7-H3 (CD276), B7-H4 (B7S1 or B7x), and B7-DC (CD273 or PD-L2) with low-to-absent expression of B7-1 (CD80) and B7-2 (CD86) [7–10] (Fig. 2).”
§ T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment > T cell anergy
What the sources say
- Not checked yetcites [1] Zou W Immunosuppressive networks in the tumour environment and their therapeutic relevance Nat Rev Cancer 2005 5 263 274 15776005 source
- Not checked yetcites [3] Pardoll DM The blockade of immune checkpoints in cancer immunotherapy Nat Rev Cancer 2012 12 252 264 22437870 PMC4856023 source
- Not checked yetcites [7] Zou W Chen L Inhibitory B7-family molecules in the tumour microenvironment Nat Rev Immunol 2008 8 467 477 18500231 source
- Not checked yetcites [8] Blank C Brown I Peterson AC Spiotto M Iwai Y Honjo T Gajewski TF PD-L1/B7H-1 inhibits the effector phase of tumor rejection by T cell receptor (TCR) transgenic CD8+ T cells Cancer Res 2004 64 1140 1145 14871849 source
- Not checked yetcites [9] source
- Not checked yetcites [10] Kryczek I Zou L Rodriguez P Zhu G Wei S Mottram P Brumlik M Cheng P Curiel T Myers L B7-H4 expression identifies a novel suppressive macrophage population in human ovarian carcinoma J Exp Med 2006 203 871 881 16606666 PMC2118300 source
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- Also stated in: § T cell anergy · plain
In the paper
“Specifically, sole binding of TCR by MHC promotes Ca2+ imbalance on T cells and retention of active-RAP-1 in the cytosol, an imbalance that would normally be corrected by co-stimulation through CD28 (Ras/MAPK) [**19,20].”
§ T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment > T cell anergy
What the sources say
- Not checked yetcites [**19,20]
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In the paper
“Recent clinical trials have validated that blockade of B7-H1/PD-1 signaling is a meaningful immune therapeutic regimen [**32,**33].”
§ T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment > T cell exhaustion
What the sources say
- Not checked yetcites [**32,**33]
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In the paper
“Early growth response gene 2 (Egr2) may be a central transcription factor that regulates T cell anergic state [*18].”
§ T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment > T cell anergy
What the sources say
- Not checked yetcites [*18]
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“blockade of B7-H1/PD-1 pathway was investigated as therapeutic targets in solid human tumors [9,30]”
§ T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment > T cell exhaustion
What the sources say
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Galectin-9 is the Tim-3 ligand.”
§ T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment > T cell senescence
What the sources say
- Not checked yetcites [65] Zhu C Anderson AC Schubart A Xiong H Imitola J Khoury SJ Zheng XX Strom TB Kuchroo VK The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity Nat Immunol 2005 6 1245 1252 16286920 source
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In the paper
“Similar findings were obtained in patients with melanoma [*63] and lymphoma [64].”
§ T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment > T cell senescence
What the sources say
- Not checked yetcites [*63]
- Not checked yetcites [64] Huang X Bai X Cao Y Wu J Huang M Tang D Tao S Zhu T Liu Y Yang Y Lymphoma endothelium preferentially expresses Tim-3 and facilitates the progression of lymphoma by mediating immune evasion J Exp Med 2010 207 505 520 20176801 PMC2839144 source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“However, high levels of senescent T cells were found in younger patients with autoimmune disease and chronic viral infection [54].”
§ T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment > T cell senescence
What the sources say
- Not checked yetcites [54] Pawelec G Solana R Immunoageing - the cause or effect of morbidity Trends Immunol 2001 22 348 349 11505929 source
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In the paper
“In addition to low expression of CD28, high expression of Tim-3, CD57, killer cell lectin-like receptor subfamily G, member 1 (KLRG-1) are thought to be associated with T cell senescence [40,60–64](Fig. 2).”
§ T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment > T cell senescence
What the sources say
- Not checked yetcites [40] Li H Wu K Tao K Chen L Zheng Q Lu X Liu J Shi L Liu C Wang G Tim-3/galectin-9 signaling pathway mediates T-cell dysfunction and predicts poor prognosis in patients with hepatitis B virus-associated hepatocellular carcinoma Hepatology 2012 56 1342 1351 22505239 source
- Not checked yetcites [60] Brenchley JM Karandikar NJ Betts MR Ambrozak DR Hill BJ Crotty LE Casazza JP Kuruppu J Migueles SA Connors M Expression of CD57 defines replicative senescence and antigen-induced apoptotic death of CD8+ T cells Blood 2003 101 2711 2720 12433688 source
- Not checked yetcites [61] source
- Not checked yetcites [62] Voehringer D Blaser C Brawand P Raulet DH Hanke T Pircher H Viral infections induce abundant numbers of senescent CD8 T cells J Immunol 2001 167 4838 4843 11673487 source
- Not checked yetcites [63] source
- Not checked yetcites [64] Huang X Bai X Cao Y Wu J Huang M Tang D Tao S Zhu T Liu Y Yang Y Lymphoma endothelium preferentially expresses Tim-3 and facilitates the progression of lymphoma by mediating immune evasion J Exp Med 2010 207 505 520 20176801 PMC2839144 source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“In line with this notion, tumor cells can induce T cell senescence in in vitro co-cultures [56].”
§ T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment > T cell senescence
What the sources say
- Not checked yetcites [56] Montes CL Chapoval AI Nelson J Orhue V Zhang X Schulze DH Strome SE Gastman BR Tumor-induced senescent T cells with suppressor function: a potential form of tumor immune evasion Cancer Res 2008 68 870 879 18245489 source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“in patients with HCC, the expression of PD-1 and Tim-3 is minimally overlapping in tumor infiltrating T cells.”
§ T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment > T cell exhaustion
What the sources say
- Not checked yetcites [40] Li H Wu K Tao K Chen L Zheng Q Lu X Liu J Shi L Liu C Wang G Tim-3/galectin-9 signaling pathway mediates T-cell dysfunction and predicts poor prognosis in patients with hepatitis B virus-associated hepatocellular carcinoma Hepatology 2012 56 1342 1351 22505239 source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Notably, exhausted T cells may highly express multiple “inhibitory” receptors, including PD-1, 2B4 (CD244), BTLA, CTLA-4, CD160, LAG-3 and Tim-3 [38,42,43,45].”
§ T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment > T cell exhaustion
What the sources say
- Not checked yetcites [38] Blackburn SD Shin H Haining WN Zou T Workman CJ Polley A Betts MR Freeman GJ Vignali DA Wherry EJ Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection Nat Immunol 2009 10 29 37 19043418 PMC2605166 source
- Not checked yetcites [42] Fourcade J Sun Z Pagliano O Guillaume P Luescher IF Sander C Kirkwood JM Olive D Kuchroo V Zarour HM CD8(+) T cells specific for tumor antigens can be rendered dysfunctional by the tumor microenvironment through upregulation of the inhibitory receptors BTLA and PD-1 Cancer Res 2012 72 887 896 22205715 PMC3288235 source
- Not checked yetcites [43] Derre L Rivals JP Jandus C Pastor S Rimoldi D Romero P Michielin O Olive D Speiser DE BTLA mediates inhibition of human tumor-specific CD8+ T cells that can be partially reversed by vaccination J Clin Invest 2010 120 157 167 20038811 PMC2799219 source
- Not checked yetcites [45] Woo SR Turnis ME Goldberg MV Bankoti J Selby M Nirschl CJ Bettini ML Gravano DM Vogel P Liu CL Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape Cancer Res 2012 72 917 927 22186141 PMC3288154 source
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In the paper
“blockade of these surface molecules allows rescue of their effector functions as shown by cell cycle progression and acquired effector cytokine expression and cytotoxicity [40,43,44].”
§ T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment > T cell exhaustion
What the sources say
- Not checked yetcites [40] Li H Wu K Tao K Chen L Zheng Q Lu X Liu J Shi L Liu C Wang G Tim-3/galectin-9 signaling pathway mediates T-cell dysfunction and predicts poor prognosis in patients with hepatitis B virus-associated hepatocellular carcinoma Hepatology 2012 56 1342 1351 22505239 source
- Not checked yetcites [43] Derre L Rivals JP Jandus C Pastor S Rimoldi D Romero P Michielin O Olive D Speiser DE BTLA mediates inhibition of human tumor-specific CD8+ T cells that can be partially reversed by vaccination J Clin Invest 2010 120 157 167 20038811 PMC2799219 source
- Not checked yetcites [44] Jin HT Anderson AC Tan WG West EE Ha SJ Araki K Freeman GJ Kuchroo VK Ahmed R Cooperation of Tim-3 and PD-1 in CD8 T-cell exhaustion during chronic viral infection Proc Natl Acad Sci U S A 2010 107 14733 14738 20679213 PMC2930455 source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“These studies support the concept that certain subsets of memory T cells endow the capability both to self-renew and to generate more effector T cells.”
§ T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment > T cell stemness
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In the paper
“More recent mouse work has shown that by blocking T cell differentiation, Wnt signaling promoted the generation of this memory stem cell population [70].”
§ T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment > T cell stemness
What the sources say
- Not checked yetcites [70] Gattinoni L Zhong XS Palmer DC Ji Y Hinrichs CS Yu Z Wrzesinski C Boni A Cassard L Garvin LM Wnt signaling arrests effector T cell differentiation and generates CD8+ memory stem cells Nat Med 2009 15 808 813 19525962 PMC2707501 source
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In the paper
“The capacity to continuously generate effector memory T cells will replenish the effector memory T cell pool, and help maintain a constant repertoire of memory T cells for a human lifetime, despite the finite lifespan of individual effector cells and reduced thymus function [68].”
§ T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment > T cell stemness
What the sources say
- Not checked yetcites [68] Lanzavecchia A Sallusto F Progressive differentiation and selection of the fittest in the immune response Nat Rev Immunol 2002 2 982 987 12461571 source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“DNA damage can cause mouse thymic precursor lymphocytes to withdraw from the cell cycle and undergo senescence [59].”
§ T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment > T cell senescence
What the sources say
- Not checked yetcites [59] Van Nguyen T Puebla-Osorio N Pang H Dujka ME Zhu C DNA damage-induced cellular senescence is sufficient to suppress tumorigenesis: a mouse model J Exp Med 2007 204 1453 1461 17535972 PMC2118600 source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In conclusion, peripheral T cell tolerance mechanisms including regulatory T cells, T cell anergy, exhaustion, and senescence impair ongoing T cell immunity and enable tumor immune escape.”
§ T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment > Conclusions
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In the paper
“In conclusion, peripheral T cell tolerance mechanisms including regulatory T cells, T cell anergy, exhaustion, and senescence impair ongoing T cell immunity and enable tumor immune escape.”
§ T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment > Conclusions
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In the paper
“Although these cell subsets are conceptually distinct, they may be functionally and phenotypically overlapped.”
§ T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment > Conclusions
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In the paper
“Compelling evidence demonstrates the co-existence of T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment.”
§ T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment > Conclusions
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In the paper
“It suggests that different categories of T cell abnormalities may be mechanistically intertwined [28,74–76].”
§ T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment > Conclusions
What the sources say
- Not checked yetcites [28] Wherry EJ T cell exhaustion Nat Immunol 2011 12 492 499 21739672 source
- Not checked yetcites [74] Workman CJ Cauley LS Kim IJ Blackman MA Woodland DL Vignali DA Lymphocyte activation gene-3 (CD223) regulates the size of the expanding T cell population following antigen activation in vivo J Immunol 2004 172 5450 5455 15100286 source
- Not checked yetcites [75] Huang CT Workman CJ Flies D Pan X Marson AL Zhou G Hipkiss EL Ravi S Kowalski J Levitsky HI Role of LAG-3 in regulatory T cells Immunity 2004 21 503 513 15485628 source
- Not checked yetcites [76] Bengsch B Seigel B Ruhl M Timm J Kuntz M Blum HE Pircher H Thimme R Coexpression of PD-1, 2B4, CD160 and KLRG1 on exhausted HCV-specific CD8+ T cells is linked to antigen recognition and T cell differentiation PLoS Pathog 2010 6 e1000947 20548953 PMC2883597 source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Furthermore, these cells achieved a higher anti-tumor response when compared to effector and central memory T cells.”
§ T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment > T cell stemness
What the sources say
- Not checked yetcites [**71,**72]
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“suggesting that stemness might correlate with better immune responses.”
§ T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment > T cell stemness
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“compelling evidence indicate that dysfunctional T cells express in different degrees the “inhibitory” molecules including PD-1, Tim-3, LAG-3, 2B4, CD160, and KLGR-1.”
§ T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment > Conclusions
What the sources say
- Not checked yetcites [28] Wherry EJ T cell exhaustion Nat Immunol 2011 12 492 499 21739672 source
- Not checked yetcites [74] Workman CJ Cauley LS Kim IJ Blackman MA Woodland DL Vignali DA Lymphocyte activation gene-3 (CD223) regulates the size of the expanding T cell population following antigen activation in vivo J Immunol 2004 172 5450 5455 15100286 source
- Not checked yetcites [75] Huang CT Workman CJ Flies D Pan X Marson AL Zhou G Hipkiss EL Ravi S Kowalski J Levitsky HI Role of LAG-3 in regulatory T cells Immunity 2004 21 503 513 15485628 source
- Not checked yetcites [76] Bengsch B Seigel B Ruhl M Timm J Kuntz M Blum HE Pircher H Thimme R Coexpression of PD-1, 2B4, CD160 and KLRG1 on exhausted HCV-specific CD8+ T cells is linked to antigen recognition and T cell differentiation PLoS Pathog 2010 6 e1000947 20548953 PMC2883597 source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“For example, despite their phenotypic markers of terminal differentiation, Th17 cells have stem cell feature with powerful functionalities [71–73].”
§ T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment > Conclusions
What the sources say
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- It may state two separate claims as one. 29
- Probably not a substantial claim. 4
In the paper
“Initial mouse studies have proposed that B7-H1/PD-1 signaling pathway mediates CD8+ T cell functional exhaustion in the context of chronic infection, and PD-1 was proposed to be a marker for exhausted T cells [*29].”
§ T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment > T cell exhaustion
What the sources say
- Not checked yetcites [*29]
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Notably, activated T cells and effector T cells in the early stage may express PD-1 and remain functional [35,*36].”
§ T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment > T cell exhaustion
What the sources say
- Not checked yetcites [35,*36]
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“It has been suggested that the anergy program is initiated by improper mTOR and Ras/MAPK signaling in the cell, a pathway which lies directly downstream of TCR/CD28 engagement.”
§ T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment > T cell anergy
What the sources say
- Not checked yetcites [**19,20]
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Animal model studies have shown that introduction of B7-1 into tumors by transfection or blockade of inhibitory B7 family members can reduce tumor growth or result in spontaneous tumor rejection in vivo [7–13].”
§ T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment > T cell anergy
What the sources say
- Not checked yetcites [7] Zou W Chen L Inhibitory B7-family molecules in the tumour microenvironment Nat Rev Immunol 2008 8 467 477 18500231 source
- Not checked yetcites [8] Blank C Brown I Peterson AC Spiotto M Iwai Y Honjo T Gajewski TF PD-L1/B7H-1 inhibits the effector phase of tumor rejection by T cell receptor (TCR) transgenic CD8+ T cells Cancer Res 2004 64 1140 1145 14871849 source
- Not checked yetcites [9] source
- Not checked yetcites [10] Kryczek I Zou L Rodriguez P Zhu G Wei S Mottram P Brumlik M Cheng P Curiel T Myers L B7-H4 expression identifies a novel suppressive macrophage population in human ovarian carcinoma J Exp Med 2006 203 871 881 16606666 PMC2118300 source
- Not checked yetcites [11] Chen L Ashe S Brady WA Hellstrom I Hellstrom KE Ledbetter JA McGowan P Linsley PS Costimulation of antitumor immunity by the B7 counterreceptor for the T lymphocyte molecules CD28 and CTLA-4 Cell 1992 71 1093 1102 1335364 source
- Not checked yetcites [12] Gajewski TF B7-1 but not B7-2 efficiently costimulates CD8+ T lymphocytes in the P815 tumor system in vitro J Immunol 1996 156 465 472 8543795 source
- Not checked yetcites [13] Blank C Kuball J Voelkl S Wiendl H Becker B Walter B Majdic O Gajewski TF Theobald M Andreesen R Blockade of PD-L1 (B7-H1) augments human tumor-specific T cell responses in vitro Int J Cancer 2006 119 317 327 16482562 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“it was demonstrated that human tumor cells and/or tumor associated APCs expressed B7-H1, and B7-H1/PD-1 pathway mediated immune suppression [**9]”
§ T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment > T cell exhaustion
What the sources say
- Not checked yetcites [**9]
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“In the course of defining exhausted PD-1+ T cells, T cell immunoglobulin and mucin-domain-containing molecule-3 (Tim-3) [39,41], lymphocyte-activation gene (LAG)-3 [38], and the B and T-cell lymphocyte attenuator (BTLA, CD272) [42,43] were found to be co-expressed with PD-1, and the co-expression has been strongly correlated with immune dysfunction in patients with cancer.”
§ T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment > T cell exhaustion
What the sources say
- Not checked yetcites [39] source
- Not checked yetcites [41] Zhou Q Munger ME Veenstra RG Weigel BJ Hirashima M Munn DH Murphy WJ Azuma M Anderson AC Kuchroo VK Coexpression of Tim-3 and PD-1 identifies a CD8+ T-cell exhaustion phenotype in mice with disseminated acute myelogenous leukemia Blood 2011 117 4501 4510 21385853 PMC3099570 source
- Not checked yetcites [38] Blackburn SD Shin H Haining WN Zou T Workman CJ Polley A Betts MR Freeman GJ Vignali DA Wherry EJ Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection Nat Immunol 2009 10 29 37 19043418 PMC2605166 source
- Not checked yetcites [42] Fourcade J Sun Z Pagliano O Guillaume P Luescher IF Sander C Kirkwood JM Olive D Kuchroo V Zarour HM CD8(+) T cells specific for tumor antigens can be rendered dysfunctional by the tumor microenvironment through upregulation of the inhibitory receptors BTLA and PD-1 Cancer Res 2012 72 887 896 22205715 PMC3288235 source
- Not checked yetcites [43] Derre L Rivals JP Jandus C Pastor S Rimoldi D Romero P Michielin O Olive D Speiser DE BTLA mediates inhibition of human tumor-specific CD8+ T cells that can be partially reversed by vaccination J Clin Invest 2010 120 157 167 20038811 PMC2799219 source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“The E3 ubiquiting ligase family can affect PI3K, mTOR, and Ras/MAPK signaling pathways and help to actively maintain anergy [21,23,24].”
§ T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment > T cell anergy
What the sources say
- Not checked yetcites [21] Anandasabapathy N Ford GS Bloom D Holness C Paragas V Seroogy C Skrenta H Hollenhorst M Fathman CG Soares L GRAIL: an E3 ubiquitin ligase that inhibits cytokine gene transcription is expressed in anergic CD4+ T cells Immunity 2003 18 535 547 12705856 source
- Not checked yetcites [23] Jeon MS Atfield A Venuprasad K Krawczyk C Sarao R Elly C Yang C Arya S Bachmaier K Su L Essential role of the E3 ubiquitin ligase Cbl-b in T cell anergy induction Immunity 2004 21 167 177 15308098 source
- Not checked yetcites [24] Mueller DL E3 ubiquitin ligases as T cell anergy factors Nat Immunol 2004 5 883 890 15334084 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Homeostatic proliferation of anti-tumor T cells in a lymphopenic host both reverses anergy and promotes tumor rejection in vivo [14].”
§ T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment > T cell anergy
What the sources say
- Not checked yetcites [14] Brown IE Blank C Kline J Kacha AK Gajewski TF Homeostatic proliferation as an isolated variable reverses CD8+ T cell anergy and promotes tumor rejection J Immunol 2006 177 4521 4529 16982889 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“The effects of this imbalance on the genetic reprogramming of these cells have been hypothesized to be mediated by NFAT homodimer formation and transcription of anergy-inducing genes [21,22].”
§ T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment > T cell anergy
What the sources say
- Not checked yetcites [21] Anandasabapathy N Ford GS Bloom D Holness C Paragas V Seroogy C Skrenta H Hollenhorst M Fathman CG Soares L GRAIL: an E3 ubiquitin ligase that inhibits cytokine gene transcription is expressed in anergic CD4+ T cells Immunity 2003 18 535 547 12705856 source
- Not checked yetcites [22] Soto-Nieves N Puga I Abe BT Bandyopadhyay S Baine I Rao A Macian F Transcriptional complexes formed by NFAT dimers regulate the induction of T cell tolerance J Exp Med 2009 206 867 876 19307325 PMC2715123 source
hedgedconditional- Asserted: fails — The authors may not put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The authors may not put it forward as true. The paper’s conclusions may not depend on it.
In the paper
“HCC-associated Tim-3+T cells expressed reduced CD28, suggesting that these cells may be early senescence stage [40].”
§ T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment > T cell exhaustion
What the sources say
- Not checked yetcites [40] Li H Wu K Tao K Chen L Zheng Q Lu X Liu J Shi L Liu C Wang G Tim-3/galectin-9 signaling pathway mediates T-cell dysfunction and predicts poor prognosis in patients with hepatitis B virus-associated hepatocellular carcinoma Hepatology 2012 56 1342 1351 22505239 source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“In line with these limited reports in non-tumor system, human tumor associated Th17 cells expressed stem cell markers and exhibited stem cell like features.”
§ T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment > T cell stemness
What the sources say
- Not checked yetcites [**71,**72]
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Cell cycle controlling proteins p16, p21, and p53, normally inhibit cell cycle progression and have been shown to be accumulated in senescent cells [49–51].”
§ T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment > T cell senescence
What the sources say
- Not checked yetcites [49] Passos JF Nelson G Wang C Richter T Simillion C Proctor CJ Miwa S Olijslagers S Hallinan J Wipat A Feedback between p21 and reactive oxygen production is necessary for cell senescence Mol Syst Biol 2010 6 347 20160708 PMC2835567 source
- Not checked yetcites [50] Rodier F Coppe JP Patil CK Hoeijmakers WA Munoz DP Raza SR Freund A Campeau E Davalos AR Campisi J Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion Nat Cell Biol 2009 11 973 979 19597488 PMC2743561 source
- Not checked yetcites [51] Beausejour CM Krtolica A Galimi F Narita M Lowe SW Yaswen P Campisi J Reversal of human cellular senescence: roles of the p53 and p16 pathways EMBO J 2003 22 4212 4222 12912919 PMC175806 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“Telomere shortening is an inherent byproduct of cellular division, which affects cellular function and leads to cell senescence [48].”
§ T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment > T cell senescence
What the sources say
- Not checked yetcites [48] Hayflick L Moorhead PS The serial cultivation of human diploid cell strains Exp Cell Res 1961 25 585 621 13905658 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“The concept of T cell stemness was initially stemmed from the observations that mouse central memory T cells are arrested at a pre-differentiation stage by transcriptional inhibitors and retain replicative potential and long-term production of effector T cells after a second antigen challenge [67].”
§ T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment > T cell stemness
What the sources say
- Not checked yetcites [67] Fearon DT Manders P Wagner SD Arrested differentiation, the self-renewing memory lymphocyte, and vaccination Science 2001 293 248 250 11452114 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Bat3 localization at this protein region allows T cells continued proliferation and IFNγ production, an effect that was lost on Bat3 deficient cells and upon Tim-3 binding to galectin-9.”
§ T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment > T cell senescence
What the sources say
- Not checked yetcites [66] Rangachari M Zhu C Sakuishi K Xiao S Karman J Chen A Angin M Wakeham A Greenfield EA Sobel RA Bat3 promotes T cell responses and autoimmunity by repressing Tim-3-mediated cell death and exhaustion Nat Med 2012 18 1394 1400 22863785 PMC3491118 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“In these studies, T cells co-expressing these surface molecules show a significant decrease in IL-2, IFNγ, and TNFα expression as well as cell cycle arrest, which defines T cell exhaustion.”
§ T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment > T cell exhaustion
What the sources say
- Not checked yetcites [39] source
- Not checked yetcites [41] Zhou Q Munger ME Veenstra RG Weigel BJ Hirashima M Munn DH Murphy WJ Azuma M Anderson AC Kuchroo VK Coexpression of Tim-3 and PD-1 identifies a CD8+ T-cell exhaustion phenotype in mice with disseminated acute myelogenous leukemia Blood 2011 117 4501 4510 21385853 PMC3099570 source
- Not checked yetcites [38] Blackburn SD Shin H Haining WN Zou T Workman CJ Polley A Betts MR Freeman GJ Vignali DA Wherry EJ Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection Nat Immunol 2009 10 29 37 19043418 PMC2605166 source
- Not checked yetcites [42] Fourcade J Sun Z Pagliano O Guillaume P Luescher IF Sander C Kirkwood JM Olive D Kuchroo V Zarour HM CD8(+) T cells specific for tumor antigens can be rendered dysfunctional by the tumor microenvironment through upregulation of the inhibitory receptors BTLA and PD-1 Cancer Res 2012 72 887 896 22205715 PMC3288235 source
- Not checked yetcites [43] Derre L Rivals JP Jandus C Pastor S Rimoldi D Romero P Michielin O Olive D Speiser DE BTLA mediates inhibition of human tumor-specific CD8+ T cells that can be partially reversed by vaccination J Clin Invest 2010 120 157 167 20038811 PMC2799219 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“It suggests that cancer associated Tim-3+ T cells may contain senescent cells and experience cell cycle arrest in G1/S phase.”
§ T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment > T cell senescence
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“In addition to phenotypic alteration, senescent T cells manifest defective killing abilities and the development of negative regulatory functions [52,53].”
§ T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment > T cell senescence
What the sources say
- Not checked yetcites [52] Appay V Nixon DF Donahoe SM Gillespie GM Dong T King A Ogg GS Spiegel HM Conlon C Spina CA HIV-specific CD8(+) T cells produce antiviral cytokines but are impaired in cytolytic function J Exp Med 2000 192 63 75 10880527 PMC1887711 source
- Not checked yetcites [53] Akbar AN Henson SM Are senescence and exhaustion intertwined or unrelated processes that compromise immunity? Nat Rev Immunol 2011 11 289 295 21436838 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“A promising aspect is that clinical blockade of B7-H1/PD-1, the key T cell exhaustion pathway, may rescue T cell effector functions in vivo, and results in significant objective clinical responses [32,33].”
§ T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment > T cell exhaustion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“human HCC- associated T cells highly express Tim-3 and cyclin dependent kinase inhibitors, and interact with galectin-9+myeloid APCs. These cells fail to enter the cell cycle [40].”
§ T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment > T cell senescence
What the sources say
- Not checked yetcites [40] Li H Wu K Tao K Chen L Zheng Q Lu X Liu J Shi L Liu C Wang G Tim-3/galectin-9 signaling pathway mediates T-cell dysfunction and predicts poor prognosis in patients with hepatitis B virus-associated hepatocellular carcinoma Hepatology 2012 56 1342 1351 22505239 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“it has been postulated that the human leukocyte antigen (HLA)-B-associated transcript 3 (Bat3) modulates Tim-3 function on T cells by interacting with Tim-3 cytoplasmic tail [66].”
§ T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment > T cell senescence
What the sources say
- Not checked yetcites [66] Rangachari M Zhu C Sakuishi K Xiao S Karman J Chen A Angin M Wakeham A Greenfield EA Sobel RA Bat3 promotes T cell responses and autoimmunity by repressing Tim-3-mediated cell death and exhaustion Nat Med 2012 18 1394 1400 22863785 PMC3491118 source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Senescent T cells are characterized by telomere shortenings, phenotypic change (loss of CD28 expression), and cell cycle arrest [46,47] (Fig. 1).”
§ T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment > T cell senescence
What the sources say
- Not checked yetcites [46] Adibzadeh M Pohla H Rehbein A Pawelec G Long-term culture of monoclonal human T lymphocytes: models for immunosenescence? Mech Ageing Dev 1995 83 171 183 8583835 source
- Not checked yetcites [47] Effros RB Replicative senescence in the immune system: impact of the Hayflick limit on T-cell function in the elderly Am J Hum Genet 1998 62 1003 1007 9545415 PMC1377102 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Phenotypically, senescent CD28−/dimCD8+T cells are observed in patients with lung cancers [57], head and neck cancer [58].”
§ T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment > T cell senescence
What the sources say
- Not checked yetcites [57] Meloni F Morosini M Solari N Passadore I Nascimbene C Novo M Ferrari M Cosentino M Marino F Pozzi E Foxp3 expressing CD4+ CD25+ and CD8+CD28− T regulatory cells in the peripheral blood of patients with lung cancer and pleural mesothelioma Hum Immunol 2006 67 1 12 16698419 source
- Not checked yetcites [58] Tsukishiro T Donnenberg AD Whiteside TL Rapid turnover of the CD8(+)CD28(−) T-cell subset of effector cells in the circulation of patients with head and neck cancer Cancer Immunol Immunother 2003 52 599 607 12827303 PMC11032778 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“In a mouse model, CD44lowCD62Lhigh memory CD8+ T cells express high levels of stem cell antigen-1 (Sca-1), Bcl-2 and common IL-2 and IL-15 receptor β chain (CD122). Because these cells showed robust self-renewal and the multipotent capacity to generate central memory and effector memory T cells, they were designated T memory stem cells [69].”
§ T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment > T cell stemness
What the sources say
- Not checked yetcites [69] Zhang Y Joe G Hexner E Zhu J Emerson SG Host-reactive CD8+ memory stem cells in graft-versus-host disease Nat Med 2005 11 1299 1305 16288282 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“This suggests that cells in younger patients may become senescent, and chronic activation and proliferation may still cause T cell senescence [55].”
§ T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment > T cell senescence
What the sources say
- Not checked yetcites [55] Vallejo AN Weyand CM Goronzy JJ T-cell senescence: a culprit of immune abnormalities in chronic inflammation and persistent infection Trends Mol Med 2004 10 119 124 15102354 source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Galectin-9 induces intracellular calcium flux, aggregation and death of Th1 cells in Tim-3-dependent manner [65].”
§ T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment > T cell senescence
What the sources say
- Not checked yetcites [65] Zhu C Anderson AC Schubart A Xiong H Imitola J Khoury SJ Zheng XX Strom TB Kuchroo VK The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity Nat Immunol 2005 6 1245 1252 16286920 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“It is arguable but experimentally operative that PD-1 may be a marker for exhausted cells, Tim-3 and KLRG-1 may be markers for senescent cells, and mouse stem-like T cells may express Sca-1 [70].”
§ T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment > Conclusions
What the sources say
- Not checked yetcites [70] Gattinoni L Zhong XS Palmer DC Ji Y Hinrichs CS Yu Z Wrzesinski C Boni A Cassard L Garvin LM Wnt signaling arrests effector T cell differentiation and generates CD8+ memory stem cells Nat Med 2009 15 808 813 19525962 PMC2707501 source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“it is evident that B7-H1/PD-1 and Tim-3/galectin-9 signaling pathways may synergistically and/or additively mediate T cell dysfunction, and simultaneous blockade of these pathways may result in improved T cell immunity.”
§ T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment > Conclusions
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Human Th17 cells were shown to give rise to distinct Th lineages, as measured through the expression of IFNγ, and Foxp3+ cells, heightened self-renewal, and survival capabilities [71,72].”
§ T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment > T cell stemness
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Interestingly, Th17 cells retain a stem cell-like phenotype through the coordinated effects of HIF1α/Notch/Bcl-2 and are also potent anti-tumor effectors [71], suggesting that stemness might correlate with better immune responses.”
§ T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment > T cell stemness
What the sources say
- Not checked yetcites [71] source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Human Th17 cells have certain “stem cell properties” at the genetic, molecular and functional levels, and are long-lived cells.”
§ T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment > T cell stemness
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“When measured for their biological activity, mouse and human Th17 cells displayed greater survival potential, persistence as well as the ability of repopulating sub-lethally irradiated mice [**71,**72].”
§ T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment > T cell stemness
What the sources say
- Not checked yetcites [**71,**72]
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper relies on this without support.
Human tumors progress despite the presence of tumor-associated antigen-specific T cells.
“Human tumors progress despite the presence of tumor associated antigen (TAA)-specific T cells.”
The paper relies on this without support.
T cell exhaustion occurs when T cells are chronically activated at sites of chronic inflammation, such as cancer, autoimmunity, and chronic infection.
“T cell exhaustion occurs when T cells are chronically activated at sites of chronic inflammation, such as cancer, autoimmunity, and chronic infection.”
The authors state this as an assumption.
The tumor microenvironment provides the necessary conditions for effector T cells to become functionally exhausted and to maintain this state during disease progression.
“Nonetheless, it is assumed that the tumor microenvironment provides the necessary conditions for effector T cells to become functionally exhausted as well as being able to maintain this state during disease progression.”
The paper relies on this without support.
These markers are not mutually exclusive or inclusive in a given T cell subset.
“However, these markers are not mutually exclusive and inclusive in a given T cell subset.”
The paper relies on this without support.
PD-1+ cells may express Tim-3 and LAG-3.
“PD-1+ cells may express Tim-3 and LAG-3.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Exhausted T cells are usually CM/EM T cells that have been chronically stimulated [341].”
From Guidelines for the use of flow cytometry and cell sorting in immunological studies (third edition) (2021) · cites this paper as [341]
Experimental — accuracy not yet measuredIn the citing paper
“More recent studies have shown that, during aging, the cytotoxic activity of immune cells decreases, and the expression of functional molecules associated with cytotoxic activity, such as interferon gamma (IFN-γ), granzyme B, and perforin, is also reduced [31–34] (Table 1).”
From Immunosenescence: a key player in cancer development (2020) · cites this paper as [31]
In the citing paper
“T cell senescence is irreversible, as opposed to their anergy and exhaustion, both of which are considered reversible [31, 38–40].”
From Immunosenescence: a key player in cancer development (2020) · cites this paper as [31]
Citations
Cites
The blockade of immune checkpoints in cancer immunotherapy
Pardoll, D. M. (2012) · Nature Reviews Cancer · doi:10.1038/nrc3239 · Cited by 13,838
Safety, activity, and immune correlates of anti–PD-1 antibody in cancer
Topalian, S. L., Hodi, F. S., Brahmer, J. R., Gettinger, S. N., Smith, D. C., McDermott, D. F., Powderly, J. D., Carvajal, R. D., Sosman, J. A., Atkins, M. B., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1200690 · Cited by 12,628
The serial cultivation of human diploid cell strains
Hayflick, L., & Moorhead, P. S. (1961) · Experimental Cell Research · doi:10.1016/0014-4827(61)90192-6 · Cited by 8,508
Safety and activity of anti-PD-L1 antibody in patients with advanced cancer
Brahmer, J. R., Tykodi, S. S., Chow, L. Q. M., Hwu, W.-J., Topalian, S. L., Hwu, P., Drake, C. G., Camacho, L. H., Kauh, J., Odunsi, K., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1200694 · Cited by 7,945
Wherry, E. J. (2011) · Nature Immunology · doi:10.1038/ni.2035 · Cited by 4,062
Restoring function in exhausted CD8 T cells during chronic viral infection
Barber, D. L., Wherry, E. J., Masopust, D., Zhu, B., Allison, J. P., Sharpe, A. H., Freeman, G. J., & Ahmed, R. (2005) · Nature · doi:10.1038/nature04444 · Cited by 4,057
Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion
Rodier, F., Coppé, J.-P., Patil, C. K., Hoeijmakers, W. A. M., Muñoz, D. P., Raza, S. R., Freund, A., Campeau, E., Davalos, A. R., & Campisi, J. (2009) · Nature Cell Biology · doi:10.1038/ncb1909 · Cited by 2,232
Molecular Signature of CD8+ T Cell Exhaustion during Chronic Viral Infection
Wherry, E. J., Ha, S.-J., Kaech, S. M., Haining, W. N., Sarkar, S., Kalia, V., Subramaniam, S., Blattman, J. N., Barber, D. L., & Ahmed, R. (2007) · Immunity · doi:10.1016/j.immuni.2007.09.006 · Cited by 2,103
Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity
Sakuishi, K., Apetoh, L., Sullivan, J. M., Blazar, B. R., Kuchroo, V. K., & Anderson, A. C. (2010) · Journal of Experimental Medicine · doi:10.1084/jem.20100643 · Cited by 2,072
Blackburn, S. D., Shin, H., Haining, W. N., Zou, T., Workman, C. J., Polley, A., Betts, M. R., Freeman, G. J., Vignali, D. A. A., & Wherry, E. J. (2009) · Nature Immunology · doi:10.1038/ni.1679 · Cited by 2,062
Cited by
Sorted by citations
Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression
Chang, C.-H., Qiu, J., O’Sullivan, D., Buck, M. D., Noguchi, T., Curtis, J. D., Chen, Q., Gindin, M., Gubin, M. M., van der Windt, G. J. W., et al. (2015) · Cell · doi:10.1016/j.cell.2015.08.016 · Cited by 3,331
Inflammation and tumor progression: signaling pathways and targeted intervention
Zhao, H., Wu, L., Yan, G., Chen, Y., Zhou, M., Wu, Y., & Li, Y. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00658-5 · Cited by 3,058
Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy
Nagarsheth, N., Wicha, M. S., & Zou, W. (2017) · Nature reviews. Immunology · doi:10.1038/nri.2017.49 · Cited by 2,251
Self-citationSenescence in Health and Disease
He, S., & Sharpless, N. E. (2017) · Cell · doi:10.1016/j.cell.2017.05.015 · Cited by 1,766
Saxena, M., van der Burg, S. H., Melief, C. J. M., & Bhardwaj, N. (2021) · Nature reviews. Cancer · doi:10.1038/s41568-021-00346-0 · Cited by 1,581
Metadata
- Authors
- Crespo, J., Sun, H., Welling, T. H., Tian, Z., & Zou, W.
- Affiliations
- University of Michigan (US)
- University of Science and Technology of China (CN)
- Corresponding author
- Tian, Zhigang
- Zou, Weiping
- Venue
- Current Opinion in Immunology
- Publisher
- Elsevier BV
- Published
- 2013-04
- Volume
- 25
- Issue
- 2
- Pages
- 214-221
- ISSN
- 0952-7915 (ISSN-L)
- PMC
- PMC3636159
- OpenAlex
- W2050558251
- Cited by
- 752
- References
- 77
- Citations by year
- 2026: 32 · 2025: 67 · 2024: 74 · 2023: 76 · 2022: 73 · 2021: 80 · 2020: 63 · 2019: 59 · 2018: 61 · 2017: 52 · 2016: 42 · 2015: 42 · 2014: 23 · 2013: 8
- FWCI
- 3.34
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Current Opinion in Immunology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5t32ai007413-32)
- National Cancer Institute (R01CA123088, R01CA152470, R01CA156685, K08CA151414, R01CA099985)
- National Institute of Allergy and Infectious Diseases (T32-AI-007413)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- T cell anergy, T cell exhaustion, T cell senescence, T cell stemness, tumor microenvironment, tumor-associated antigens, immune evasion, immunosuppression, cancer immunotherapy
- MeSH terms
- Animals, Humans, Neoplasms, Stem Cells, T-Lymphocytes, Cellular Senescence, Clonal Anergy, Tumor Microenvironment
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-06, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-06 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Statistics and arithmetic are recomputed, not judged.
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