PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: Mechanisms, response biomarkers, and combinations

PD pathway blockade elicits durable antitumor responses in a subset of patients with a broad spectrum of cancers. Gloss PD-L1 and PD-1 (PD) pathway blockade is a highly promising therapy and has elicited durable antitumor responses and long-term remissions in a subset of patients with a broad spectrum of cancers. How to improve, widen, and predict the clinical response to anti-PD therapy is a central theme in the field of cancer immunology and immunotherapy. Oncologic, immunologic, genetic, and biological studies focused on the human cancer microenvironment have yielded substantial insight into this issue. Here, we focus on tumor microenvironment and evaluate several potential therapeutic response markers including the PD-L1 and PD-1 expression pattern, genetic mutations within cancer cells and neoantigens, cancer epigenetics and effector T cell landscape, and microbiota. We further clarify the mechanisms of action of these markers and their roles in shaping, being shaped, and/or predicting therapeutic responses. We also discuss a variety of combinations with PD pathway blockade and their scientific rationales for cancer treatment. PD-L1 and PD-1 (PD) pathway blockade is a highly promising therapy and has elicited durable antitumor responses and long-term remissions in a subset of patients with a broad spectrum of cancers. How to improve, widen, and predict the clinical response to anti-PD therapy is a central theme in the field of cancer immunology and immunotherapy. Oncologic, immunologic, genetic, and biological studies focused on the human cancer microenvironment have yielded substantial insight into this issue. Here, we focus on tumor microenvironment and evaluate several potential therapeutic response markers including the PD-L1 and PD-1 expression pattern, genetic mutations within cancer cells and neoantigens, cancer epigenetics and effector T cell landscape, and microbiota. We further clarify the mechanisms of action of these markers and their roles in shaping, being shaped, and/or predicting therapeutic responses. We also discuss a variety of combinations with PD pathway blockade and their scientific rationales for cancer treatment.

[1]  L. Crinò,et al.  Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. , 2015, The New England journal of medicine.

[2]  J. Locasale,et al.  Phosphoenolpyruvate Is a Metabolic Checkpoint of Anti-tumor T Cell Responses , 2015, Cell.

[3]  T. Curiel,et al.  Plasmacytoid dendritic cells induce CD8+ regulatory T cells in human ovarian carcinoma. , 2005, Cancer research.

[4]  D. Schadendorf,et al.  Improved survival with ipilimumab in patients with metastatic melanoma. , 2010, The New England journal of medicine.

[5]  G. Freeman,et al.  Therapeutic PD-1 pathway blockade augments with other modalities of immunotherapy T-cell function to prevent immune decline in ovarian cancer. , 2013, Cancer research.

[6]  T. Curiel,et al.  Blockade of B7-H1 improves myeloid dendritic cell–mediated antitumor immunity , 2003, Nature Medicine.

[7]  J. Cheville,et al.  618: Costimulatory B7-H1 In Renal Cell Carcinoma Patients: Indicator of Tumor Aggressiveness and Potential Therapeutic Target , 2005 .

[8]  G. Zhu,et al.  Costimulating aberrant T cell responses by B7-H1 autoantibodies in rheumatoid arthritis. , 2003, The Journal of clinical investigation.

[9]  J. Cheville,et al.  Tumor B7-H1 is associated with poor prognosis in renal cell carcinoma patients with long-term follow-up. , 2006, Cancer research.

[10]  G. Linette,et al.  Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. , 2015, The Lancet. Oncology.

[11]  Michael R Stratton,et al.  High-throughput epitope discovery reveals frequent recognition of neo-antigens by CD4+ T cells in human melanoma , 2014, Nature Medicine.

[12]  Gefeng Zhu,et al.  B7-H4 expression identifies a novel suppressive macrophage population in human ovarian carcinoma , 2006, The Journal of experimental medicine.

[13]  Israel Lowy,et al.  Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[14]  H. Schreiber,et al.  Innate and adaptive immune cells in the tumor microenvironment , 2013, Nature Immunology.

[15]  Kathleen R. Cho,et al.  Myeloid-derived suppressor cells enhance stemness of cancer cells by inducing microRNA101 and suppressing the corepressor CtBP2. , 2013, Immunity.

[16]  M. Wasik,et al.  Oncogenic kinase NPM/ALK induces through STAT3 expression of immunosuppressive protein CD274 (PD-L1, B7-H1) , 2008, Proceedings of the National Academy of Sciences.

[17]  Ke Wu,et al.  IL-17+ Regulatory T Cells in the Microenvironments of Chronic Inflammation and Cancer , 2011, The Journal of Immunology.

[18]  Z. Trajanoski,et al.  Type, Density, and Location of Immune Cells Within Human Colorectal Tumors Predict Clinical Outcome , 2006, Science.

[19]  E. Mardis,et al.  A dendritic cell vaccine increases the breadth and diversity of melanoma neoantigen-specific T cells , 2015, Science.

[20]  Lieping Chen,et al.  Kupffer cell suppression of CD8+ T cells in human hepatocellular carcinoma is mediated by B7-H1/programmed death-1 interactions. , 2009, Cancer research.

[21]  George Coukos,et al.  Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival , 2004, Nature Medicine.

[22]  M. Millenson,et al.  PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. , 2015, The New England journal of medicine.

[23]  M. Azuma,et al.  Clinical Significance of Programmed Death-1 Ligand-1 and Programmed Death-1 Ligand-2 Expression in Human Esophageal Cancer , 2005, Clinical Cancer Research.

[24]  Jason B. Williams,et al.  Up-Regulation of PD-L1, IDO, and Tregs in the Melanoma Tumor Microenvironment Is Driven by CD8+ T Cells , 2013, Science Translational Medicine.

[25]  T. Curiel,et al.  Targeting regulatory T cells , 2012, Targeted Oncology.

[26]  L. Gordon,et al.  Disabling immune tolerance by programmed death-1 blockade with pidilizumab after autologous hematopoietic stem-cell transplantation for diffuse large B-cell lymphoma: results of an international phase II trial. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[27]  Derek S. Chan,et al.  Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti–PD-L1 immunotherapy in pancreatic cancer , 2013, Proceedings of the National Academy of Sciences.

[28]  R. Weichselbaum,et al.  Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. , 2014, The Journal of clinical investigation.

[29]  J. Moyer,et al.  Human TH17 Cells Are Long-Lived Effector Memory Cells , 2011, Science Translational Medicine.

[30]  T. Welling,et al.  T Cells and Costimulation in Cancer , 2013, Cancer journal.

[31]  W. Zou,et al.  Regulatory T-cell compartmentalization and trafficking. , 2006, Blood.

[32]  Philipp Koehn.  Decoding , 2012, Encyclopedia of Algorithms.

[33]  F. Balkwill,et al.  Epithelial cancer cell migration: a role for chemokine receptors? , 2001, Cancer research.

[34]  D. Rosenberg,et al.  Multifaceted roles of PGE2 in inflammation and cancer , 2012, Seminars in Immunopathology.

[35]  David C. Smith,et al.  Overall Survival and Long-Term Safety of Nivolumab (Anti-Programmed Death 1 Antibody, BMS-936558, ONO-4538) in Patients With Previously Treated Advanced Non-Small-Cell Lung Cancer. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[36]  J. Taube,et al.  Association of PD-1, PD-1 Ligands, and Other Features of the Tumor Immune Microenvironment with Response to Anti–PD-1 Therapy , 2014, Clinical Cancer Research.

[37]  J. Castle,et al.  Mutant MHC class II epitopes drive therapeutic immune responses to cancer , 2015, Nature.

[38]  Maxim N. Artyomov,et al.  Checkpoint Blockade Cancer Immunotherapy Targets Tumour-Specific Mutant Antigens , 2014, Nature.

[39]  X. Lu,et al.  Tim‐3/galectin‐9 signaling pathway mediates T‐cell dysfunction and predicts poor prognosis in patients with hepatitis B virus‐associated hepatocellular carcinoma , 2012, Hepatology.

[40]  Jenna M. Sullivan,et al.  Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity , 2010, The Journal of experimental medicine.

[41]  F. Cappuzzo,et al.  Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. , 2015, The Lancet. Oncology.

[42]  NK cell-based immunotherapy for malignant diseases , 2013, Cellular and Molecular Immunology.

[43]  Qiang Yu,et al.  Pharmacologic disruption of Polycomb-repressive complex 2-mediated gene repression selectively induces apoptosis in cancer cells. , 2007, Genes & development.

[44]  T. Schumacher,et al.  Neoantigens in cancer immunotherapy , 2015, Science.

[45]  J. Larkin,et al.  Pembrolizumab versus Ipilimumab in Advanced Melanoma. , 2015, The New England journal of medicine.

[46]  C. Drake,et al.  Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. , 2012, The New England journal of medicine.

[47]  M. Croft,et al.  Signaling through OX40 (CD134) breaks peripheral T-cell tolerance , 2001, Nature Medicine.

[48]  R. J. Kelleher,et al.  Response to Comment on “Characterization of Human Lung Tumor-Associated Fibroblasts and Their Ability to Modulate the Activation of Tumor-Associated T Cells” , 2007, The Journal of Immunology.

[49]  A. Alavi,et al.  A Phase I Study of an Agonist CD40 Monoclonal Antibody (CP-870,893) in Combination with Gemcitabine in Patients with Advanced Pancreatic Ductal Adenocarcinoma , 2013, Clinical Cancer Research.

[50]  S. Rosenberg,et al.  Cancer immunotherapy: moving beyond current vaccines , 2004, Nature Medicine.

[51]  G. Zhu,et al.  B7-H3 Enhances Tumor Immunity In Vivo by Costimulating Rapid Clonal Expansion of Antigen-Specific CD8+ Cytolytic T Cells1 , 2004, The Journal of Immunology.

[52]  R. Weichselbaum,et al.  Therapeutic effects of ablative radiation on local tumor require CD8+ T cells: changing strategies for cancer treatment. , 2009, Blood.

[53]  David C. Gondek,et al.  VISTA, a novel mouse Ig superfamily ligand that negatively regulates T cell responses , 2011, The Journal of experimental medicine.

[54]  S. Lebecque,et al.  Dendritic Cells Infiltrating Human Non-Small Cell Lung Cancer Are Blocked at Immature Stage1 , 2007, The Journal of Immunology.

[55]  Erik Sahai,et al.  Cyclooxygenase-Dependent Tumor Growth through Evasion of Immunity , 2015, Cell.

[56]  Peter A. Jones,et al.  Alterations of immune response of non-small cell lung cancer with Azacytidine , 2013, Oncotarget.

[57]  C. Horak,et al.  Safety, efficacy, and biomarkers of nivolumab with vaccine in ipilimumab-refractory or -naive melanoma. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[58]  D. Schadendorf,et al.  Pooled Analysis of Long-Term Survival Data From Phase II and Phase III Trials of Ipilimumab in Unresectable or Metastatic Melanoma. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[59]  T. Welling,et al.  Tumor-associated macrophages produce interleukin 6 and signal via STAT3 to promote expansion of human hepatocellular carcinoma stem cells. , 2014, Gastroenterology.

[60]  Antoni Ribas,et al.  Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial , 2014, The Lancet.

[61]  D. Birnbaum,et al.  CXCR1 blockade selectively targets human breast cancer stem cells in vitro and in xenografts. , 2010, The Journal of clinical investigation.

[62]  Lieping Chen,et al.  Coinhibitory receptor PD-1H preferentially suppresses CD4⁺ T cell-mediated immunity. , 2014, The Journal of clinical investigation.

[63]  Jimmy Lin,et al.  Mining Exomic Sequencing Data to Identify Mutated Antigens Recognized by Adoptively Transferred Tumor-reactive T cells , 2013, Nature Medicine.

[64]  E. Mardis,et al.  Cancer Exome Analysis Reveals a T Cell Dependent Mechanism of Cancer Immunoediting , 2012, Nature.

[65]  J. Mulé,et al.  Blockade of Programmed Death Ligand 1 Enhances the Therapeutic Efficacy of Combination Immunotherapy against Melanoma , 2010, The Journal of Immunology.

[66]  D. Holdstock.  Past, present--and future? , 2005, Medicine, conflict, and survival.

[67]  Xue Han,et al.  Anti-PD-1/PD-L1 therapy of human cancer: past, present, and future. , 2015, The Journal of clinical investigation.

[68]  J. Wolchok,et al.  Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti–CTLA-4 therapy against melanoma , 2013, The Journal of experimental medicine.

[69]  M. Greene,et al.  The therapeutic effect of anti-HER2/neu antibody depends on both innate and adaptive immunity. , 2010, Cancer cell.

[70]  Eric Vivier,et al.  The Intestinal Microbiota Modulates the Anticancer Immune Effects of Cyclophosphamide , 2013, Science.

[71]  N. Mitsiades,et al.  Fas ligand expression in thyroid carcinomas: a potential mechanism of immune evasion. , 1999, The Journal of clinical endocrinology and metabolism.

[72]  David C. Smith,et al.  Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. , 2014, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[73]  Yoshimasa Tanaka,et al.  Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer , 2007, Proceedings of the National Academy of Sciences.

[74]  T. Curiel,et al.  Stromal-derived factor-1 in human tumors recruits and alters the function of plasmacytoid precursor dendritic cells , 2001, Nature Medicine.

[75]  David C. Smith,et al.  Survival, Durable Response, and Long-Term Safety in Patients With Previously Treated Advanced Renal Cell Carcinoma Receiving Nivolumab. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[76]  Drew M. Pardoll,et al.  The blockade of immune checkpoints in cancer immunotherapy , 2012, Nature Reviews Cancer.

[77]  J. Hackney,et al.  The immunoreceptor TIGIT regulates antitumor and antiviral CD8(+) T cell effector function. , 2014, Cancer cell.

[78]  S. Stevanović,et al.  A vaccine targeting mutant IDH1 induces antitumour immunity , 2014, Nature.

[79]  C. Drake,et al.  Stereotactic Radiation Therapy Augments Antigen-Specific PD-1–Mediated Antitumor Immune Responses via Cross-Presentation of Tumor Antigen , 2014, Cancer Immunology Research.

[80]  L. Zitvogel,et al.  Decoding Cell Death Signals in Inflammation and Immunity , 2010, Cell.

[81]  R. Davis,et al.  Safety and activity of PD1 blockade by pidilizumab in combination with rituximab in patients with relapsed follicular lymphoma: a single group, open-label, phase 2 trial. , 2014, The Lancet. Oncology.

[82]  R. Emerson,et al.  PD-1 blockade induces responses by inhibiting adaptive immune resistance , 2014, Nature.

[83]  Michael S. Goldberg,et al.  Decitabine Enhances Lymphocyte Migration and Function and Synergizes with CTLA-4 Blockade in a Murine Ovarian Cancer Model , 2015, Cancer Immunology Research.

[84]  S. Anand,et al.  B7-H1/CD80 interaction is required for the induction and maintenance of peripheral T-cell tolerance. , 2010, Blood.

[85]  G. Zhu,et al.  Tumor-associated B7-H1 promotes T-cell apoptosis: A potential mechanism of immune evasion , 2002, Nature Medicine.

[86]  A. Chang,et al.  Tumor-induced immune suppression of in vivo effector T-cell priming is mediated by the B7-H1/PD-1 axis and transforming growth factor beta. , 2008, Cancer research.

[87]  Y. Dou,et al.  PRC2 Epigenetically Silences Th1-Type Chemokines to Suppress Effector T-Cell Trafficking in Colon Cancer. , 2016, Cancer research.

[88]  S. Rosenberg,et al.  Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. , 2009, Blood.

[89]  Wen-rong Gong,et al.  Cutting Edge: IFN-γ Enables APC to Promote Memory Th17 and Abate Th1 Cell Development1 , 2008, The Journal of Immunology.

[90]  P. Mischel,et al.  Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma , 2007, Nature Medicine.

[91]  Y. Dou,et al.  IL-22(+)CD4(+) T cells promote colorectal cancer stemness via STAT3 transcription factor activation and induction of the methyltransferase DOT1L. , 2014, Immunity.

[92]  Andrew P. Feinberg,et al.  Cancer as a dysregulated epigenome allowing cellular growth advantage at the expense of the host , 2013, Nature Reviews Cancer.

[93]  P. Sharma,et al.  PD-L 1 Expression in Triple-Negative Breast Cancer , 2014 .

[94]  T. Gajewski,et al.  Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity , 2015, Nature.

[95]  J. Kirkwood,et al.  Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen–specific CD8+ T cell dysfunction in melanoma patients , 2010, The Journal of experimental medicine.

[96]  Kathleen R. Cho,et al.  Epigenetic silencing of Th1 type chemokines shapes tumor immunity and immunotherapy , 2015, Nature.

[97]  G. Freeman,et al.  Restoring function in exhausted CD8 T cells during chronic viral infection , 2006, Nature.

[98]  G. Linette,et al.  Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. , 2015, The New England journal of medicine.

[99]  Yan Liu,et al.  EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations , 2012, Nature.

[100]  N. Xu,et al.  Immunohistochemical localization of programmed death-1 ligand-1 (PD-L1) in gastric carcinoma and its clinical significance. , 2006, Acta histochemica.

[101]  Z. Trajanoski,et al.  Effector memory T cells, early metastasis, and survival in colorectal cancer. , 2005, The New England journal of medicine.

[102]  Gang Wu,et al.  Hydrogel dual delivered celecoxib and anti-PD-1 synergistically improve antitumor immunity , 2016, Oncoimmunology.

[103]  M. Banerjee,et al.  Phenotype, distribution, generation, and functional and clinical relevance of Th17 cells in the human tumor environments. , 2009, Blood.

[104]  G. Zhu,et al.  B7-H1 is a ubiquitous antiapoptotic receptor on cancer cells. , 2008, Blood.

[105]  K. Knutson,et al.  Accumulation of memory precursor CD8 T cells in regressing tumors following combination therapy with vaccine and anti-PD-1 antibody. , 2014, Cancer research.

[106]  N. Hacohen,et al.  Molecular and Genetic Properties of Tumors Associated with Local Immune Cytolytic Activity , 2015, Cell.

[107]  K. Schäkel,et al.  Low-dose irradiation programs macrophage differentiation to an iNOS⁺/M1 phenotype that orchestrates effective T cell immunotherapy. , 2013, Cancer cell.

[108]  R. Herbst,et al.  Programmed death ligand-1 expression in non-small cell lung cancer , 2014, Laboratory Investigation.

[109]  G. Freeman,et al.  Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. , 2007, Immunity.

[110]  T. Honjo,et al.  Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. , 1996, International immunology.

[111]  S. Rosenberg,et al.  Clinical Scale Zinc Finger Nuclease-mediated Gene Editing of PD-1 in Tumor Infiltrating Lymphocytes for the Treatment of Metastatic Melanoma. , 2015, Molecular therapy : the journal of the American Society of Gene Therapy.

[112]  I. Weissman,et al.  Engineering high-affinity PD-1 variants for optimized immunotherapy and immuno-PET imaging , 2015, Proceedings of the National Academy of Sciences.

[113]  Peter Vogel,et al.  Microenvironment and Immunology Immune Inhibitory Molecules Lag-3 and Pd-1 Synergistically Regulate T-cell Function to Promote Tumoral Immune Escape , 2022 .

[114]  D. Munn,et al.  Ido expression by dendritic cells: tolerance and tryptophan catabolism , 2004, Nature Reviews Immunology.

[115]  George Coukos,et al.  Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. , 2003, The New England journal of medicine.

[116]  R. J. Kelleher,et al.  Characterization of Human Lung Tumor-Associated Fibroblasts and Their Ability to Modulate the Activation of Tumor-Associated T Cells1 , 2007, The Journal of Immunology.

[117]  F. Ginhoux,et al.  Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota , 2015, Science.

[118]  M. Taniwaki,et al.  Multicenter phase II study of mogamulizumab (KW-0761), a defucosylated anti-cc chemokine receptor 4 antibody, in patients with relapsed peripheral T-cell lymphoma and cutaneous T-cell lymphoma. , 2014, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[119]  M. Delorenzi,et al.  Cancer cell–autonomous contribution of type I interferon signaling to the efficacy of chemotherapy , 2014, Nature Medicine.

[120]  M. Smyth,et al.  Targeting CD73 Enhances the Antitumor Activity of Anti-PD-1 and Anti-CTLA-4 mAbs , 2013, Clinical Cancer Research.

[121]  I. Stratford,et al.  Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade. , 2014, Cancer research.

[122]  D. Rimm,et al.  Characterization of PD-L1 Expression and Associated T-cell Infiltrates in Metastatic Melanoma Samples from Variable Anatomic Sites , 2015, Clinical Cancer Research.

[123]  Troy Guthrie,et al.  Talimogene Laherparepvec Improves Durable Response Rate in Patients With Advanced Melanoma. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[124]  Martin L. Miller,et al.  Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer , 2015, Science.

[125]  S. Signoretti,et al.  Correlation of PD-L1 Tumor Expression and Treatment Outcomes in Patients with Renal Cell Carcinoma Receiving Sunitinib or Pazopanib: Results from COMPARZ, a Randomized Controlled Trial , 2014, Clinical Cancer Research.

[126]  S. Qiu,et al.  B7-H3 is expressed in human hepatocellular carcinoma and is associated with tumor aggressiveness and postoperative recurrence , 2012, Cancer Immunology, Immunotherapy.

[127]  G. Freeman,et al.  Blockade of Programmed Death-1 Ligands on Dendritic Cells Enhances T Cell Activation and Cytokine Production 1 , 2003, The Journal of Immunology.

[128]  H. Ishwaran,et al.  Radiation and Dual Checkpoint Blockade Activates Non-Redundant Immune Mechanisms in Cancer , 2015, Nature.

[129]  Lieve Moons,et al.  CXCL12 and vascular endothelial growth factor synergistically induce neoangiogenesis in human ovarian cancers. , 2005, Cancer research.

[130]  N. Morris,et al.  Science gone translational: the OX40 agonist story , 2011, Immunological reviews.

[131]  T. Jacks,et al.  Expression of tumour-specific antigens underlies cancer immunoediting , 2011, Nature.

[132]  Philip J. R. Goulder,et al.  PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression , 2006, Nature.

[133]  Lieping Chen,et al.  Inhibitory B7-family molecules in the tumour microenvironment , 2008, Nature Reviews Immunology.

[134]  J. Taube,et al.  Durable Cancer Regression Off-Treatment and Effective Reinduction Therapy with an Anti-PD-1 Antibody , 2012, Clinical Cancer Research.

[135]  P. Hegde,et al.  MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer , 2014, Nature.

[136]  Bert Vogelstein,et al.  PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. , 2015, The New England journal of medicine.

[137]  B. Vogelstein,et al.  PD-1 blockade in tumors with mismatch repair deficiency. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[138]  Christopher J. Kane,et al.  Immunosuppressive plasma cells impede T cell-dependent immunogenic chemotherapy , 2015, Nature.

[139]  M. Ladanyi,et al.  A Phase 2 Single Arm Trial of Cabozantinib in Patients with Advanced RET-Rearranged Lung Cancers , 2016, The Lancet. Oncology.

[140]  D. Douek,et al.  PD-1 identifies the patient-specific CD8⁺ tumor-reactive repertoire infiltrating human tumors. , 2014, The Journal of clinical investigation.

[141]  George F. Murphy,et al.  Melanoma Cell-Intrinsic PD-1 Receptor Functions Promote Tumor Growth , 2015, Cell.

[142]  G. Freeman,et al.  Engagement of the Pd-1 Immunoinhibitory Receptor by a Novel B7 Family Member Leads to Negative Regulation of Lymphocyte Activation , 2000, The Journal of experimental medicine.

[143]  W. Zou.  Regulatory T cells, tumour immunity and immunotherapy , 2006, Nature Reviews Immunology.

[144]  G. Freeman,et al.  Combination cancer immunotherapy and new immunomodulatory targets , 2015, Nature Reviews Drug Discovery.

[145]  G. Zhu,et al.  B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion , 1999, Nature Medicine.

[146]  Jason B. Williams,et al.  Commensal Bifidobacterium promotes antitumor immunity and facilitates anti–PD-L1 efficacy , 2015, Science.

[147]  R. Schreiber,et al.  Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression , 2015, Cell.

[148]  Weiping Zou,et al.  Immunosuppressive networks in the tumour environment and their therapeutic relevance , 2005, Nature Reviews Cancer.

[149]  A. Chang,et al.  Effects of Tumor Irradiation on Host T-Regulatory Cells and Systemic Immunity in the Context of Adoptive T-Cell Therapy in Mice , 2013, Journal of immunotherapy.

[150]  A. Qattan,et al.  The B7-H1 (PD-L1) T lymphocyte-inhibitory molecule is expressed in breast cancer patients with infiltrating ductal carcinoma: correlation with important high-risk prognostic factors. , 2006, Neoplasia.

[151]  Mithat Gönen,et al.  The JAK2/STAT3 signaling pathway is required for growth of CD44⁺CD24⁻ stem cell-like breast cancer cells in human tumors. , 2011, The Journal of clinical investigation.

[152]  Lloyd J. Old,et al.  Tumor-infiltrating NY-ESO-1–specific CD8+ T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer , 2010, Proceedings of the National Academy of Sciences.

[153]  D. Schadendorf,et al.  Nivolumab in previously untreated melanoma without BRAF mutation. , 2015, The New England journal of medicine.

[154]  F. Marincola,et al.  Commensal Bacteria Control Cancer Response to Therapy by Modulating the Tumor Microenvironment , 2013, Science.

[155]  B7-H4 Expression by Nonhematopoietic Cells in the Tumor Microenvironment Promotes Antitumor Immunity , 2014, Cancer Immunology Research.

[156]  Lieping Chen,et al.  Monoclonal antibodies against the 4-1BB T-cell activation molecule eradicate established tumors , 1997, Nature Medicine.

[157]  Joe-Marc Chauvin,et al.  TIGIT and PD-1 impair tumor antigen-specific CD8⁺ T cells in melanoma patients. , 2015, The Journal of clinical investigation.

[158]  C. Drake,et al.  Immune checkpoint blockade: a common denominator approach to cancer therapy. , 2015, Cancer cell.

[159]  J. Lunceford,et al.  Pembrolizumab for the treatment of non-small-cell lung cancer. , 2015, The New England journal of medicine.

[160]  C. Horak,et al.  Nivolumab plus ipilimumab in advanced melanoma. , 2013, The New England journal of medicine.

[161]  H. Kohrt,et al.  Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients , 2014, Nature.

[162]  S. Varambally,et al.  Cancer mediates effector T cell dysfunction by targeting microRNAs and EZH2 via glycolysis restriction , 2015, Nature Immunology.

[163]  K. Shimada,et al.  Clinical importance of B7-H3 expression in human pancreatic cancer , 2009, British Journal of Cancer.

[164]  P. Sharma,et al.  PD-L1 Expression in Triple-Negative Breast Cancer , 2014, Cancer Immunology Research.

[165]  A. Korman,et al.  Programmed death-1 blockade enhances expansion and functional capacity of human melanoma antigen-specific CTLs. , 2007, International immunology.

[166]  Lieping Chen,et al.  Mechanistic Assessment of PD-1H Coinhibitory Receptor–Induced T Cell Tolerance to Allogeneic Antigens , 2015, The Journal of Immunology.

[167]  Loise M. Francisco,et al.  RGMb is a novel binding partner for PD-L2 and its engagement with PD-L2 promotes respiratory tolerance , 2014, The Journal of experimental medicine.

[168]  Jing Xu,et al.  Activated monocytes in peritumoral stroma of hepatocellular carcinoma foster immune privilege and disease progression through PD-L1 , 2009, The Journal of experimental medicine.

[169]  L. Ciuffreda,et al.  Journal of Translational Medicine BioMed Central Commentary Synopsis of the 6th Walker's Cay Colloquium on Cancer Vaccines , 2004 .

[170]  David T. W. Jones,et al.  Signatures of mutational processes in human cancer , 2013, Nature.

[171]  S. Rosenberg.  Decade in review—cancer immunotherapy: Entering the mainstream of cancer treatment , 2014, Nature Reviews Clinical Oncology.

[172]  Antoni Ribas,et al.  Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. , 2013, The New England journal of medicine.

[173]  D. Santini,et al.  IL-6 triggers malignant features in mammospheres from human ductal breast carcinoma and normal mammary gland. , 2007, The Journal of clinical investigation.

[174]  K. Odunsi,et al.  Intertumor and Intratumor NY-ESO-1 Expression Heterogeneity Is Associated with Promoter-Specific and Global DNA Methylation Status in Ovarian Cancer , 2008, Clinical Cancer Research.

[175]  J. Byrd,et al.  Phase I study of the anti-CD40 humanized monoclonal antibody lucatumumab (HCD122) in relapsed chronic lymphocytic leukemia , 2012, Leukemia & lymphoma.

[176]  J. Cheville,et al.  Costimulatory B7-H1 in renal cell carcinoma patients: Indicator of tumor aggressiveness and potential therapeutic target. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[177]  G. Zhu,et al.  Relationship between B7-H4, regulatory T cells, and patient outcome in human ovarian carcinoma. , 2007, Cancer research.

[178]  C. Divino,et al.  The novel role of tyrosine kinase inhibitor in the reversal of immune suppression and modulation of tumor microenvironment for immune-based cancer therapies. , 2009, Cancer research.

[179]  David C. Smith,et al.  Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. , 2012, The New England journal of medicine.

[180]  Peter A. Jones,et al.  Immune regulation by low doses of the DNA methyltransferase inhibitor 5-azacitidine in common human epithelial cancers , 2014, Oncotarget.

[181]  M. Valsecchi.  Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. , 2015, The New England journal of medicine.

[182]  L. Zitvogel,et al.  Cyclophosphamide induces differentiation of Th17 cells in cancer patients. , 2011, Cancer research.

[183]  S. Rosenberg,et al.  Cancer Immunotherapy Based on Mutation-Specific CD4+ T Cells in a Patient with Epithelial Cancer , 2014, Science.

[184]  K. Kinzler,et al.  The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints , 2015, Journal of Immunotherapy for Cancer.

[185]  Alison P. Klein,et al.  Colocalization of Inflammatory Response with B7-H1 Expression in Human Melanocytic Lesions Supports an Adaptive Resistance Mechanism of Immune Escape , 2012, Science Translational Medicine.