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Cited by 1,360Cancer Immunotherapy and BiomarkersImmunotherapy and Immune ResponsesT-cell and B-cell Immunology

Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations

Open access
Seidel, Judith A., Otsuka, Atsushi, Kabashima, Kenji·2018·Frontiers in Oncology
DOI 10.3389/fonc.2018.00086PMC PMC5883082
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Abstract

Melanoma, a skin cancer associated with high mortality rates, is highly radio- and chemotherapy resistant but can also be very immunogenic. These circumstances have led to a recent surge in research into therapies aiming to boost anti-tumor immune responses in cancer patients. Among these immunotherapies, neutralizing antibodies targeting the immune checkpoints T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) are being hailed as particularly successful. These antibodies have resulted in dramatic improvements in disease outcome and are now clinically approved in many countries. However, the majority of advanced stage melanoma patients do not respond or will relapse, and the hunt for the "magic bullet" to treat the disease continues. This review examines the mechanisms of action and the limitations of anti-PD-1/PD-L1 and anti-CTLA-4 antibodies which are the two types of checkpoint inhibitors currently available to patients and further explores the future avenues of their use in melanoma and other cancers.

AI snapshot

Written from the paper’s full text.

TL;DR

This review summarizes mechanisms, efficacy, and limitations of anti-PD-1/PD-L1 and anti-CTLA-4 checkpoint inhibitors in cancer, especially melanoma. It concludes these therapies improve outcomes but many advanced-stage patients do not respond or relapse, and better biomarkers and combination strategies are needed.

Key findings

  • In a Phase III melanoma trial, anti-PD-1 nivolumab produced better response (44%) and progression-free survival (6.9 months) than anti-CTLA-4 ipilimumab (19% and 2.8 months); combined nivolumab plus ipilimumab produced even higher response (58%) and survival (11.5 months).
  • Severe side effects were more frequent with anti-CTLA-4 (27.3%) than anti-PD-1 (16.3%), and highest with combination therapy (55%).
  • Checkpoint inhibitors appear most effective in patients with pre-existing anti-tumor immunity, including T cell-infiltrated tumors or high mutation rates; PD-L1 expression was correlated with efficacy in melanoma but not consistently in squamous cell carcinoma, non-small cell lung cancer, and Merkel cell carcinoma.
  • Resistance can arise through acquired tumor mutations causing loss of IFN-γ response elements or MHC class I, upregulation of alternative inhibitory receptors such as VISTA or TIM-3, and tumor-associated macrophage-mediated removal of anti-PD-1 antibody from T cells.

Methods

  • Narrative review of the mechanisms of action, clinical efficacy, adverse events, biomarkers, limitations, and future avenues of anti-PD-1/PD-L1 and anti-CTLA-4 therapies.
  • Synthesizes preclinical immunology and clinical trial data across cancers including melanoma, renal cell carcinoma, Hodgkin’s lymphoma, head and neck squamous-cell carcinoma, non-small cell lung cancer, ovarian cancer, Merkel cell carcinoma, colorectal cancer, and urothelial carcinoma.
  • Main analysis is qualitative synthesis, with tabulated trial outcomes in Table 2 and biomarkers in Table 3; no systematic review, meta-analysis, or new primary data are reported.

Limitations

  • The paper states that many patients eventually relapse or develop tumor progression despite initial checkpoint inhibitor response, and that mechanisms of acquired resistance remain incompletely understood.
  • The paper states that biomarker relationships are inconsistent across tumor types and patients, that accessing tumor tissue may be difficult especially after treatment, and that more studies are needed to identify effective biomarkers or biomarker combinations.
  • Evident from the text: this is a review rather than a primary study, and some tabulated data are incomplete or unavailable, including “n/a” entries and no published efficacy data yet for anti-PD-L1 antibodies avelumab and durvalumab.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.3389/fonc.2018.00086

Cites

Statistics

Nothing to recompute.

Claims the paper makes

0 of 178 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    Both CTLA-4 and PD-1 checkpoint inhibitors have resulted in increased patient survival in melanoma, renal cell carcinoma, squamous cell carcinoma, and non-small cell lung cancer compared to conventional chemotherapies.

    “Both CTLA-4 and PD-1 checkpoint inhibitors have resulted in increased patient survival in a number of studies, including studies on melanoma, renal cell carcinoma, squamous cell carcinoma, and non-small cell lung cancer, when compared to conventional chemotherapies (summarized in Table 2).”
    Quote in the paperSubstantial claim
  • Premisecitation

    Exhausted T cells can occur in cancer, not only in chronic viral infections.

    “Originally described in the context of chronic viral infections, where the host fails to clear the pathogen, it is now apparent that exhausted T cells can also occur in cancer (12, 13).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [12] Day, 2006, PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression, Nature source

      Not checked in the free run.

    • cites [13] Baitsch, 2011, Exhaustion of tumor-specific CD8+ T cells in metastases from melanoma patients, J Clin Invest source

      Not checked in the free run.

  • Premisecitation

    Established tumors often arise through selection of clones able to evade the immune system (immunoediting).

    “Established tumors are often thought to arise through the selection of clones that are able to evade the immune system, a process known as immunoediting (3).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] Teng, 2015, From mice to humans: developments in cancer immunoediting, J Clin Invest source

      Not checked in the free run.

  • Premisenone given

    CD8+ T cells become licensed effector cells after appropriate stimulation by antigen-presenting cells that have collected antigens at the tumor site.

    “CD8+ T cells become licensed effector cells after appropriate stimulation by antigen-presenting cells that have collected antigens at the tumor site.”
    Quote in the paperNot a substantial claim
  • Premisecitation

    Tumor cells may evade immune recognition by downregulating tumor antigens or MHC class I.

    “Tumor cells may evade immune recognition directly by downregulating features that make them vulnerable such as tumor antigens or MHC class I (4–6).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [4] Otsuka, 2015, Hedgehog pathway inhibitors promote adaptive immune responses in basal cell carcinoma, Clin Cancer Res source

      Not checked in the free run.

    • cites [5] Otsuka, 2015, Hedgehog signaling in basal cell carcinoma, J Dermatol Sci source

      Not checked in the free run.

    • cites [6] Zaretsky, 2016, Mutations associated with acquired resistance to PD-1 blockade in melanoma, N Engl J Med source

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  • May combine two claims. 37
  • Classified as probably not a substantial claim. 9

  • May combine two claims.

    Premisecitation

    Tumor antigens include normal proteins overexpressed by cancer cells and novel proteins generated by mutation and gene rearrangement.

    “These antigens include normal proteins overexpressed by cancer cells and novel proteins that are generated by mutation and gene rearrangement (1).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] Lawrence, 2013, Mutational heterogeneity in cancer and the search for new cancer-associated genes, Nature source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    Immunotherapies target the tumor indirectly by boosting anti-tumor immune responses that spontaneously arise in many patients, unlike radio- and chemotherapy which directly interfere with tumor cell growth and survival.

    “Unlike radio- and chemotherapy, which aim to directly interfere with tumor cell growth and survival, immunotherapies target the tumor indirectly by boosting the anti-tumor immune responses that spontaneously arise in many patients.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Melanoma is highly radio- and chemotherapy resistant but can also be very immunogenic.

  • May combine two claims.

    Premisereasoning

    Inhibitory receptors (immune checkpoints) and their ligands are found on a wide range of cell types and are essential for central and peripheral tolerance.

    “Inhibitory receptors, also known as immune checkpoints, and their ligands can be found on a wide range of cell types. They are essential for central and peripheral tolerance in that they counteract simultaneous activating signaling through co-stimulatory molecules.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Exhaustion is both a physiological mechanism to limit immunopathology during persistent infection and a major obstacle for anti-tumor immune responses.

    “Exhaustion is therefore both a physiological mechanism designed to limit immunopathology during persistent infection and a major obstacle for anti-tumor immune responses (17).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [17] Speiser, 2014, T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion?, Nat Rev Immunol source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    PD-1 has two ligands: PD-L1 and PD-L2.

    “PD-1 has two ligands: PD-L1 (B7-H1; CD274) and PD-L2 (B7-DC; CD273).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Other cell types such as B cells, myeloid dendritic cells, mast cells, and Langerhans cells can express PD-1.

    “Other cell types, such as B cells, myeloid dendritic cells, mast cells, and Langerhans cells, can also express PD-1 which may regulate their own and bystander cell functions under pathophysiological conditions (35–38).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [35] Peña-Cruz, 2010, PD-1 on immature and PD-1 ligands on migratory human Langerhans cells regulate antigen-presenting cell activity, J Invest Dermatol source

      Not checked in the free run.

    • cites [36] Thibult, 2013, PD-1 is a novel regulator of human B-cell activation, Int Immunol source

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    • cites [37] Lim, 2016, PD-1 expression on dendritic cells suppresses CD8+ T cell function and antitumor immunity, Oncoimmunology source

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    • cites [38] Rodrigues, 2016, Tolerogenic IDO+ dendritic cells are induced by PD-1-expressing mast cells, Front Immunol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PD-1 signaling results in reduced cytokine production (IL-2, IFN-γ, TNF-α), cell cycle progression, pro-survival Bcl-xL expression, and reduced expression of transcription factors T-bet and Eomes.

    “By interfering with early TCR/CD28 signaling and associated IL-2-dependent positive feedback, PD-1 signaling therefore results in reduced cytokine production [such as IL-2, IFN-γ, and tumor necrosis factor (TNF)-α], cell cycle progression, and pro-survival Bcl-xL gene expression, as well as reduced expression of the transcription factors involved in effector functions such as T-bet and Eomes (42,”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [42] Patsoukis, 2012, Selective effects of PD-1 on Akt and Ras pathways regulate molecular components of the cell cycle and inhibit T cell proliferation, Sci Signal source

      Not checked in the free run.

    • cites [43] Chemnitz, 2004, SHP-1 and SHP-2 associate with immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary human T cell stimulation, but only receptor ligation prevents T cell activation, J Immunol source

      Not checked in the free run.

    • cites [46] Carter, 2002, PD-1:PD-L inhibitory pathway affects both CD4+ and CD8+ T cells and is overcome by IL-2, Eur J Immunol source

      Not checked in the free run.

    • cites [47] Nurieva, 2006, T-cell tolerance or function is determined by combinatorial costimulatory signals, EMBO J source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Polymorphisms within the CTLA-4 gene are associated with autoimmune diseases in humans.

    “Similarly, polymorphisms within the CTLA-4 gene are associated with autoimmune diseases in humans (27).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27] Gough, 2005, CTLA4 gene polymorphism and autoimmunity, Immunol Rev source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Some T cell populations constitutively express PD-1 in humans and mice, for example follicular helper T cells.

    “In both humans and mice some T cell populations constitutively express PD-1; one example is follicular helper T cells (32).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] Sage, 2013, The receptor PD-1 controls follicular regulatory T cells in the lymph nodes and blood, Nat Immunol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CTLA-4 is constitutively expressed by Tregs and can be upregulated by other T cell subsets, especially CD4+ T cells, upon activation.

    “It is constitutively expressed by Tregs but can also be upregulated by other T cell subsets, especially CD4+ T cells, upon activation (21).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] Chan, 2014, Differential CTLA-4 expression in human CD4+ versus CD8+ T cells is associated with increased NFAT1 and inhibition of CD4+ proliferation, Genes Immun source

      Not checked in the free run.

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    Premisecitation

    PD-1 is homologous to CD28, primarily involved in inhibitory immune signaling, and an essential regulator of adaptive immune responses.

    “It has since become clear, however, that PD-1, which is homologous to CD28, is primarily involved in inhibitory immune signaling, and is an essential regulator of adaptive immune responses (31).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [31] Nishimura, 1999, Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor, Immunity source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    PD-L1 and PD-L2 are found on antigen-presenting cells and differentially expressed on various non-lymphoid tissues.

    “Both can be found on the surface of antigen-presenting cells (such as dendritic cells, macrophages, and monocytes), but are otherwise differentially expressed on various non-lymphoid tissues (39, 40).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [39] Latchman, 2001, PD-L2 is a second ligand for PD-1 and inhibits T cell activation, Nat Immunol source

      Not checked in the free run.

    • cites [40] Freeman, 2006, Reinvigorating exhausted HIV-specific T cells via PD-1–PD-1 ligand blockade, J Exp Med source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    CTLA-4 is a B7/CD28 family member that inhibits T cell functions.

    “CTLA-4 (CD152) is a B7/CD28 family member that inhibits T cell functions.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    PD-1 is crucial for maintenance of peripheral tolerance and for containing immune responses to avoid immunopathology.

    “Overall, PD-1 is crucial for the maintenance of peripheral tolerance and for containing immune responses to avoid immunopathology.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    CTLA-4 expression on tumors has been associated with decreased survival in nasopharyngeal carcinoma and increased survival in non-small cell lung cancer.

    “So far, the expression of CTLA-4 on tumors has been associated with decreased survival in nasopharyngeal carcinoma (54) and increased survival in non-small cell lung cancer (53).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [54] Huang, 2016, Tumor CTLA-4 overexpression predicts poor survival in patients with nasopharyngeal carcinoma, Oncotarget source

      Not checked in the free run.

    • cites [53] Salvi, 2012, Evaluation of CTLA-4 expression and relevance as a novel prognostic factor in patients with non-small cell lung cancer, Cancer Immunol Immunother source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    PD-L1 expression may be indicative of active anti-tumor immune responses and may also actively contribute to local immunosuppression.

    “PD-L1 expression may therefore be indicative of active anti-tumor immune responses and may also actively contribute to local immunosuppression.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Tumor-associated macrophages express PD-1 in mice and humans with colorectal cancer and impair macrophage phagocytosis.

    “Tumor-associated macrophages were also recently shown to express PD-1 in both mice and humans with colorectal cancer and to impair macrophage phagocytosis (59).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [59] Gordon, 2017, PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity, Nature source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a Phase III trial, nivolumab (anti-PD-1) produced better response (44%) and progression-free survival (6.9 months) than ipilimumab (19% and 2.8 months).

    “A direct comparison between the two checkpoint inhibitors in a Phase III clinical trial found better response (44%) and survival rates (6.9 months progression-free survival) among patients treated with the anti-PD-1 antibody nivolumab than among those treated with the anti-CTLA-4 antibody ipilimumab (19% and 2.8 months).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [67] Larkin, 2015, Combined nivolumab and ipilimumab or monotherapy in untreated melanoma, N Engl J Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Combined nivolumab and ipilimumab resulted in higher response rates (58%) and survival (11.5 months).

    “Combined administration of both nivolumab and ipilimumab resulted in even higher response rates (58%) and survival (11.5 months) (67).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [67] Larkin, 2015, Combined nivolumab and ipilimumab or monotherapy in untreated melanoma, N Engl J Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PD-1 has been detected on circulating tumor-specific T cells and tumor-infiltrating lymphocytes, where it was associated with decreased T cell function in humans and mice.

    “The inhibitory receptor has been detected on both circulating tumor-specific T cells and tumor-infiltrating lymphocytes, where it was associated with decreased T cell function in humans and mice (13, 29, 55–57).”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [13] Baitsch, 2011, Exhaustion of tumor-specific CD8+ T cells in metastases from melanoma patients, J Clin Invest source

      Not checked in the free run.

    • cites [29] Curran, 2010, PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors, Proc Natl Acad Sci U S A source

      Not checked in the free run.

    • cites [55] Ahmadzadeh, 2009, Tumor antigen–specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired, Blood source

      Not checked in the free run.

    • cites [56] Chapon, 2011, Progressive upregulation of PD-1 in primary and metastatic melanomas associated with blunted TCR signaling in infiltrating T lymphocytes, J Invest Dermatol source

      Not checked in the free run.

    • cites [57] Saito, 2013, Increased PD-1 expression on CD4+ and CD8+ T cells is involved in immune evasion in gastric cancer, J Surg Oncol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    High PD-1 and/or PD-L1 may correlate with poor prognosis in some cancers (melanoma, renal cell carcinoma, esophageal, gastric, ovarian) and with improved prognosis in others (angiosarcoma, gastric cancer).

    “High PD-1 and/or PD-L1 may correlate with poor prognosis in some cancers (including melanoma, renal cell carcinoma, esophageal, gastric, and ovarian cancers) and with improved prognosis in others (such as angiosarcoma and gastric cancer) (55, 60–65).”
    Quote in the paperNot a substantial claim0 of 7 sources checked
    • cites [55] Ahmadzadeh, 2009, Tumor antigen–specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired, Blood source

      Not checked in the free run.

    • cites [60] Honda, 2016, Infiltration of PD-1-positive cells in combination with tumor site PD-L1 expression is a positive prognostic factor in cutaneous angiosarcoma, Oncoimmunology source

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    • cites [61] Hino, 2010, Tumor cell expression of programmed cell death-1 ligand 1 is a prognostic factor for malignant melanoma, Cancer source

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    • cites [62] Hamanishi, 2015, Safety and antitumor activity of anti–PD-1 antibody, nivolumab, in patients with platinum-resistant ovarian cancer, J Clin Oncol source

      Not checked in the free run.

    • cites [63] Inman, 2007, PD-L1 (B7-H1) expression by urothelial carcinoma of the bladder and BCG-induced granulomata, Cancer source

      Not checked in the free run.

    • cites [64] Kim, 2016, Prognostic implications of immunosuppressive protein expression in tumors as well as immune cell infiltration within the tumor microenvironment in gastric cancer, Gastric Cancer source

      Not checked in the free run.

    • cites [65] Zhang, 2015, Prognostic significance of programmed cell death 1 (PD-1) or PD-1 ligand 1 (PD-L1) expression in epithelial-originated cancer: a meta-analysis, Medicine source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Tumor-infiltrating PD-1-expressing regulatory B cells produced IL-10; higher proportions correlated with worse disease outcome in hepatocellular carcinoma patients.

    “Another study identified a population of tumor-infiltrating PD-1-expressing regulatory B cells that produced IL-10; higher proportions of these cells were correlated with worse disease outcome in hepatocellular carcinoma patients (58).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [58] Xiao, 2016, PD-1hi identifies a novel regulatory b-cell population in human hepatoma that promotes disease progression, Cancer Discov source

      Not checked in the free run.

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    Premisecitation

    Mice deficient in PD-1 initially appear healthy but develop autoimmune diseases such as lupus-like proliferative glomerulonephritis and arthritis with age and exacerbated inflammation during infections.

    “Mice deficient in the receptor initially appear healthy, but develop autoimmune diseases such as lupus-like proliferative glomerulonephritis and arthritis with age and exacerbated inflammation during infections (18, 31, 49, 50).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [18] Erickson, 2012, Viral acute lower respiratory infections impair CD8+ T cells through PD-1, J Clin Invest source

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    • cites [31] Nishimura, 1999, Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor, Immunity source

      Not checked in the free run.

    • cites [49] Nishimura, 1998, Immunological studies on PD-1 deficient mice: implication of PD-1 as a negative regulator for B cell responses, Int Immunol source

      Not checked in the free run.

    • cites [50] Salama, 2003, Critical role of the programmed death-1 (PD-1) pathway in regulation of experimental autoimmune encephalomyelitis, J Exp Med source

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  • May combine two claims.

    Premisecitation

    PD-1 can be upregulated transiently during stimulation and constitutively during chronic immune activation.

    “PD-1 can be upregulated transiently during stimulation and constitutively during chronic immune activation (17).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] Speiser, 2014, T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion?, Nat Rev Immunol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Presence of certain bacterial strains, particularly Bacteroides fragilis, promoted Th1 polarization and was associated with improved anti-tumor immune response in animals.

    “Further experiments showed that the presence of certain bacterial strains, in particular Bacteroides fragilis, promoted Th1 polarization in the animals and was associated with an improved anti-tumor immune response (97).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [97] Vétizou, 2015, Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota, Science source

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  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    PD-1 and CTLA-4 prevent autoimmunity and limit immune activation to prevent bystander damage under physiological conditions.

    “PD-1 and CTLA-4 prevent autoimmunity and limit immune activation to prevent bystander damage under physiological conditions.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    The mutational burden of tumor cells may increase their antigenicity but may also enhance their ability to evade treatment-induced immune responses.

    “The mutational burden of tumor cells may increase their antigenicity but may also enhance their ability to evade treatment-induced immune responses.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Type I immune responses, including IFN-γ production and cytotoxic T cell functions, are important for effective anti-tumor immune responses and are associated with better responses to anti-CTLA-4 and anti-PD-1 treatments.

    “Type I immune responses, which include IFN-γ production and cytotoxic T cell functions, are important for effective anti-tumor immune responses and are associated with better responses to anti-CTLA-4 and anti-PD-1 treatments.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    PD-1 and CTLA-4 blockade may affect T helper cell profiles directly or by influencing the microbiota.

    “PD-1 and CTLA-4 blockade may also affect T helper cell profiles directly or by influencing the microbiota.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Patients with smaller tumors or low serum LDH levels at baseline have a better prognosis and are more likely to respond to anti-PD-1 treatment.

    “For example, patients with smaller tumors or low serum lactate dehydrogenase (LDH) levels at baseline have a better prognosis and are also more likely to respond to anti-PD-1 treatment (66).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [66] Ribas, 2016, Association of pembrolizumab with tumor response and survival among patients with advanced melanoma, JAMA source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Circulating tumor DNA (ctDNA) contains melanoma-associated mutations, can be released by dead tumor cells, and can be detected in serum of some patients.

    “Circulating tumor DNA (ctDNA), which contains melanoma-associated mutations and can be released by dead tumor cells, can be detected in the serum of some patients.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Particularly severe side effects may require cessation of treatment, although these patients may still respond thereafter.

    “Particularly severe side effects may require cessation of treatment, although these patients may still respond thereafter (102).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [102] Zou, 2016, PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: mechanisms, response biomarkers, and combinations, Sci Transl Med source

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  • May combine two claims.

    Premisenone given

    Presence of neoantigens on mutated tumor cells boosts anti-tumor immunogenicity and improves treatment efficacy.

    “The presence of neoantigens on mutated tumor cells boosts anti-tumor immunogenicity and improves treatment efficacy.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Pre-treatment factors associated with improved treatment responses include high eosinophil and lymphocyte blood counts, abundance of CD8+ T cells infiltrating tumor or at tumor margin, and increased serum TGF-β levels in melanoma patients treated with anti-PD-1.

    “Other pre-treatment immunological factors associated with improved treatment responses include high eosinophil and lymphocyte blood counts, an abundance of CD8+ T cells infiltrating the tumor or present at the tumor margin, and increased serum TGF-β levels in melanoma patients treated with anti-PD-1 (88, 91, 92, 109).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [88] Tumeh, 2014, PD-1 blockade induces responses by inhibiting adaptive immune resistance, Nature source

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    • cites [91] Nonomura, 2017, ADAMTSL5 Is upregulated in melanoma tissues in patients with idiopathic psoriasis vulgaris induced by nivolumab, J Eur Acad Dermatol Venereol source

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    • cites [92] Nonomura, 2016, Peripheral blood Th9 cells are a possible pharmacodynamic biomarker of nivolumab treatment efficacy in metastatic melanoma patients, Oncoimmunology source

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    • cites [109] Weide, 2016, Baseline biomarkers for outcome of melanoma patients treated with pembrolizumab, Clin Cancer Res source

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    Premisecitation

    Patients have experienced exacerbation of pre-existing autoimmune conditions such as psoriasis or development of new ones such as type 1 diabetes mellitus after immune checkpoint inhibitor treatment.

    “There have also been reports of patients experiencing exacerbation of pre-existing autoimmune conditions such as psoriasis (91, 92, 100) or developing new ones such as type 1 diabetes mellitus (101).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [91] Nonomura, 2017, ADAMTSL5 Is upregulated in melanoma tissues in patients with idiopathic psoriasis vulgaris induced by nivolumab, J Eur Acad Dermatol Venereol source

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    • cites [92] Nonomura, 2016, Peripheral blood Th9 cells are a possible pharmacodynamic biomarker of nivolumab treatment efficacy in metastatic melanoma patients, Oncoimmunology source

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    • cites [100] Kato, 2016, Exacerbation of psoriasis vulgaris during nivolumab for oral mucosal melanoma, J Eur Acad Dermatol Venereol source

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    • cites [101] Chae, 2016, A case of pembrolizumab-induced type-1 diabetes mellitus and discussion of immune checkpoint inhibitor-induced type 1 diabetes, Cancer Immunol Immunother source

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    Premisecitation

    An increase in CD8+ T cell proliferation within the tumor lesion and an increased frequency of Th9 cells in circulation were associated with treatment response.

    “An increase in CD8+ T cell proliferation within the tumor lesion and an increased frequency of Th9 cells in the patients’ circulation were also associated with treatment response (88, 91, 92).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [88] Tumeh, 2014, PD-1 blockade induces responses by inhibiting adaptive immune resistance, Nature source

      Not checked in the free run.

    • cites [91] Nonomura, 2017, ADAMTSL5 Is upregulated in melanoma tissues in patients with idiopathic psoriasis vulgaris induced by nivolumab, J Eur Acad Dermatol Venereol source

      Not checked in the free run.

    • cites [92] Nonomura, 2016, Peripheral blood Th9 cells are a possible pharmacodynamic biomarker of nivolumab treatment efficacy in metastatic melanoma patients, Oncoimmunology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Anti-PD-1-treated patients with colorectal cancers that were mismatch-repair deficient or non-small cell lung cancers with high mutation rates had better outcomes.

    “This was particularly noted in anti-CTLA-4-treated melanoma patients whose tumors displayed neo-antigens (87) and similarly in anti-PD-1-treated patients with colorectal cancers or non-small cell lung cancers that were mismatch-repair deficient or had high mutation rates, respectively (78, 86).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [78] Le, 2015, PD-1 blockade in tumors with mismatch-repair deficiency, N Engl J Med source

      Not checked in the free run.

    • cites [86] Rizvi, 2015, Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer, Science source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    PD-1 and CTLA-4 blocking agents are not effective in all patients, and even initial responders can relapse.

    “PD-1 and CTLA-4 blocking agents are not effective in all patients, and even those patients who do respond initially can relapse, highlighting the need for improved or alternative treatments.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    Not all biomarkers listed may be equally effective, and patients may still respond despite contrary biomarker-based predictions.

    “However, not all biomarkers listed here may be equally effective, and patients may still respond to treatment despite contrary biomarker-based predictions.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In anti-PD-1-treated mice with lung cancer, TIM-3 (but not VISTA) was upregulated on T cells; TIM-3 was also upregulated on T cells in adenocarcinoma patients refractory to PD-1 treatment.

    “Another study noted the upregulation of the inhibitory receptor TIM-3 (but not VISTA) on the surface of T cells in anti-PD-1-treated mice with lung cancer as well as TIM-3 upregulation on T cells in adenocarcinoma patients refractory to PD-1 treatment (113).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [113] Koyama, 2016, Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints, Nat Commun source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Anti-tumor T cell function induced by PD-1 blockade in mice could be improved by a targeted increase in mitochondrial function.

    “Anti-tumor T cell function induced by PD-1 blockade in mice could also be improved by a targeted increase in mitochondrial function (120).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [120] Chamoto, 2017, Mitochondrial activation chemicals synergize with surface receptor PD-1 blockade for T cell-dependent antitumor activity, Proc Natl Acad Sci U S A source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Macrophages may interfere with anti-tumor immunity or directly restrict therapeutic antibodies.

    “Macrophages may also interfere with anti-tumor immunity or even directly restrict therapeutic antibodies (114).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [114] Arlauckas, 2017, In vivo imaging reveals a tumor-associated macrophage–mediated resistance pathway in anti–PD-1 therapy, Sci Transl Med source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Combination of anti-CTLA-4 with anti-PD-1 treatments showed superior efficacy compared to individual administration but was associated with an increase in side effects.

    “Indeed, the combination of anti-CTLA-4 with anti-PD-1 treatments showed superior efficacy compared to individual administration, but was also associated with an increase in side effects.”
    Quote in the paperNot a substantial claim
43 of 43

  • The paper relies on this without support.

    The majority of advanced stage melanoma patients do not respond to or will relapse after checkpoint inhibitor therapy.

    “However, the majority of advanced stage melanoma patients do not respond or will relapse, and the hunt for the “magic bullet” to treat the disease continues.”

  • The paper relies on this without support.

    Melanoma is highly radio- and chemotherapy resistant but can also be very immunogenic.

    “Melanoma, a skin cancer associated with high mortality rates, is highly radio- and chemotherapy resistant but can also be very immunogenic.”

  • The paper relies on this without support.

    Findings from mouse models of cancer are relevant to human cancer patients.

    “Together, these findings suggest that human patients too may benefit from appropriate management of their intestinal flora while undergoing immune checkpoint inhibitor treatment.”
3 of 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?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Lung cancer type conflicts with cited trial

    Minor

    Table 2 labels the combination-therapy trial as non-small cell lung cancer, but the title of its cited reference 85 identifies the trial as small-cell lung cancer.

  • Pembrolizumab study called an anti-PD-L1 treatment

    Minor

    The biomarker discussion calls the treatment in reference 77 anti-PD-L1, whereas Table 2 identifies that study's drug as pembrolizumab targeting PD-1.

  • Ipilimumab progression-free survival differs between text and table

    Minor

    For the nivolumab-versus-ipilimumab melanoma trial cited as reference 67, the text gives ipilimumab progression-free survival as 2.8 months, while Table 2 gives 2.9 months.

  • Bifidobacterium study switches from anti-PD-L1 to anti-PD-1

    Minor

    The text describes the treatment in reference 125 as anti-PD-1, but the cited reference's title identifies it as anti-PD-L1.

4 of 4

The citation lists haven’t been fetched yet

References 131 · Cited by 1,360

Research works printed but not linked: 1

  1. Kim, 2016, Prognostic implications of immunosuppressive protein expression in tumors as well as immune cell infiltration within the tumor microenvironment in gastric cancer, Gastric Cancer, 19, 42, 10.1007/s10120-014-0440-5 · DOI

Authors
Seidel, J. A., Otsuka, A., & Kabashima, K.
Affiliations
  • Kyoto University (JP)
  • Agency for Science, Technology and Research (SG)
Corresponding author
  • Otsuka, Atsushi
  • Kabashima, Kenji
ORCID
Venue
Frontiers in Oncology
Publisher
Frontiers Media SA
Published
2018-03-28
Volume
8
Pages
86-86
ISSN
2234-943X (ISSN-L)
DOI
10.3389/fonc.2018.00086
PMC
PMC5883082
OpenAlex
W2794612508
Semantic Scholar
af3cf98b70dccd06ae4124f3640d1d2712761f62
Cited by
1,360
References
131
Citations by year
2026: 70 · 2025: 122 · 2024: 208 · 2023: 204 · 2022: 212 · 2021: 187 · 2020: 207 · 2019: 129 · 2018: 20 · 2013: 1
FWCI
14.20
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Oncology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Keywords
anti-PD-1 therapy, CTLA-4 blockade, immune checkpoint inhibitors, melanoma, PD-1/PD-L1, CTLA-4, cancer immunotherapy, antitumor immunity, treatment resistance, mechanism of action

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Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

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