T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment

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].”

What the sources say

• Not checked yetcites [*29]

In the paper

“Notably, activated T cells and effector T cells in the early stage may express PD-1 and remain functional [35,*36].”

What the sources say

• Not checked yetcites [35,*36]

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.”

What the sources say

• Not checked yetcites [**19,20]

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].”

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

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]”

What the sources say

• Not checked yetcites [**9]

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.”

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

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].”

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

In the paper

“Homeostatic proliferation of anti-tumor T cells in a lymphopenic host both reverses anergy and promotes tumor rejection in vivo [14].”

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

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].”

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

In the paper

“HCC-associated Tim-3+T cells expressed reduced CD28, suggesting that these cells may be early senescence stage [40].”

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

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.”

What the sources say

• Not checked yetcites [**71,**72]

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].”

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

In the paper

“Telomere shortening is an inherent byproduct of cellular division, which affects cellular function and leads to cell senescence [48].”

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

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].”

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

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.”

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

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.”

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

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.”

In the paper

“In addition to phenotypic alteration, senescent T cells manifest defective killing abilities and the development of negative regulatory functions [52,53].”

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

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].”

What the sources say

• Not checked yetcites [32] source
• Not checked yetcites [33] source

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].”

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

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].”

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

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).”

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

In the paper

“Phenotypically, senescent CD28−/dimCD8+T cells are observed in patients with lung cancers [57], head and neck cancer [58].”

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

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].”

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

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].”

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

In the paper

“Galectin-9 induces intracellular calcium flux, aggregation and death of Th1 cells in Tim-3-dependent manner [65].”

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

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].”

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

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.”

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].”

What the sources say

• Not checked yetcites [71] source
• Not checked yetcites [72] source

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.”

What the sources say

• Not checked yetcites [71] source

In the paper

“Human Th17 cells have certain “stem cell properties” at the genetic, molecular and functional levels, and are long-lived cells.”

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].”

What the sources say

• Not checked yetcites [**71,**72]