Beyond the concept of cold and hot tumors for the development of novel predictive biomarkers and the rational design of immunotherapy combination

Immunotherapy has revolutionized the management of cancers. At the end of 2018, 1,716 clinical trials assessed regimen that combine program death‐1 (PD‐1)/program death ligand‐1 (PD‐L1) blockers with other cancer therapies (tyrosine kinase inhibitor, chemotherapy and radiotherapy). There is a contrast between these clinical dynamics and the difficulty of identifying biomarkers to better select patients that could benefit from immunotherapy. In this context, different tumor classifications have been proposed to try to better stratify patients. They rely on the characteristics of the tumor microenvironment and led first to divide them into hot and cold tumors. In this review, we aim to demonstrate the limitations of this classification focusing on the differential significance of subpopulations of intratumor CD8 + T cells. We also underline novel mechanisms of resistance to anti‐PD‐1/PD‐L1 blockade, focusing on myeloid cells, hypoxia and tumor immunoediting under treatment. Understanding the mechanisms of resistance to immune‐checkpoint inhibitor is indeed a powerful research driver that allows further identification of novel biomarkers, drug development and bring a rational to innovative therapeutic combinations.

[1]  A. Regev,et al.  Abstract PR01: A cancer cell program promotes T-cell exclusion and resistance to checkpoint blockade , 2020, Cancer Research.

[2]  J. Lunceford,et al.  Association between tissue TMB (tTMB) and clinical outcomes with pembrolizumab monotherapy (pembro) in PD-L1-positive advanced NSCLC in the KEYNOTE-010 and -042 trials , 2019, Annals of Oncology.

[3]  J. Koropatnick,et al.  AVID200 neutralizes TGF-beta1 and -beta3, the principal immunosuppressive TGF-beta isoforms overexpressed by tumours, and sensitizes tumours to immune checkpoint inhibitors , 2019, Annals of Oncology.

[4]  J. Lunceford,et al.  Pembrolizumab (pembro) plus platinum-based chemotherapy (chemo) for metastatic NSCLC: Tissue TMB (tTMB) and outcomes in KEYNOTE-021, 189, and 407 , 2019, Annals of Oncology.

[5]  G. Curigliano,et al.  Phase (Ph) II study of MBG453 + spartalizumab in patients (pts) with non-small cell lung cancer (NSCLC) and melanoma pretreated with anti–PD-1/L1 therapy , 2019, Annals of Oncology.

[6]  H. Rammensee,et al.  PD-1 and LAG-3 Dominate Checkpoint Receptor–Mediated T-cell Inhibition in Renal Cell Carcinoma , 2019, Cancer Immunology Research.

[7]  Martin L. Miller,et al.  UVB-Induced Tumor Heterogeneity Diminishes Immune Response in Melanoma , 2019, Cell.

[8]  S. Moestrup,et al.  Specific targeting of CD163+ TAMs mobilizes inflammatory monocytes and promotes T cell–mediated tumor regression , 2019, The Journal of experimental medicine.

[9]  D. Kuang,et al.  The local immune landscape determines tumor PD-L1 heterogeneity and sensitivity to therapy. , 2019, The Journal of clinical investigation.

[10]  Shisong Ma,et al.  Aurora-A inhibition eliminates myeloid cell-mediated immunosuppression and enhances the efficacy of anti-PD-L1 therapy in breast cancer. , 2019, Cancer research.

[11]  Michael C. Schmid,et al.  Macrophage-Mediated Subversion of Anti-Tumour Immunity , 2019, Cells.

[12]  L. Esserman,et al.  Abstract CT003: Analysis of immune cell infiltrates as predictors of response to the checkpoint inhibitor pembrolizumab in the neoadjuvant I-SPY 2 TRIAL , 2019, Clinical Trials.

[13]  E. King,et al.  Single-cell transcriptomic analysis of tissue-resident memory T cells in human lung cancer , 2019, The Journal of experimental medicine.

[14]  Yong Liu,et al.  TOX is a critical regulator of tumour-specific T cell differentiation , 2019, Nature.

[15]  C. Rubio-Perez,et al.  LIF regulates CXCL9 in tumor-associated macrophages and prevents CD8+ T cell tumor-infiltration impairing anti-PD1 therapy , 2019, Nature Communications.

[16]  G. Coukos,et al.  Targeting Adenosine in Cancer Immunotherapy to Enhance T-Cell Function , 2019, Front. Immunol..

[17]  R. Greil,et al.  Protocol-specified final analysis of the phase 3 KEYNOTE-048 trial of pembrolizumab (pembro) as first-line therapy for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). , 2019, Journal of Clinical Oncology.

[18]  Howard Y. Chang,et al.  Clonal replacement of tumor-specific T cells following PD-1 blockade , 2019, Nature Medicine.

[19]  Daniel K. Wells,et al.  Tumor Characteristics Associated with Benefit from Pembrolizumab in Advanced Non–Small Cell Lung Cancer , 2019, Clinical Cancer Research.

[20]  K. Shannon,et al.  Comprehensive molecular profiling of metastatic melanoma to predict response to monotherapy and combination immunotherapy. , 2019, Journal of Clinical Oncology.

[21]  K. Kelly,et al.  First-in-human study of REGN3767 (R3767), a human LAG-3 monoclonal antibody (mAb), ± cemiplimab in patients (pts) with advanced malignancies. , 2019, Journal of Clinical Oncology.

[22]  L. Galluzzi,et al.  TIM-3 Dictates Functional Orientation of the Immune Infiltrate in Ovarian Cancer , 2019, Clinical Cancer Research.

[23]  R. Herbst,et al.  Expression Analysis and Significance of PD-1, LAG-3, and TIM-3 in Human Non–Small Cell Lung Cancer Using Spatially Resolved and Multiparametric Single-Cell Analysis , 2019, Clinical Cancer Research.

[24]  B. Dai,et al.  Tumor-associated Macrophage-derived Interleukin-23 Interlinks Kidney Cancer Glutamine Addiction with Immune Evasion. , 2019, European urology.

[25]  A. Bikfalvi,et al.  Beyond the tumour microenvironment , 2019, International journal of cancer.

[26]  A. Mantovani,et al.  One Clever Macrophage Checkpoint , 2019, Clinical Cancer Research.

[27]  E. V. Van Allen,et al.  Genomic correlates of response to immune checkpoint blockade , 2019, Nature Medicine.

[28]  P. Keegan,et al.  FDA Approval Summary: Pembrolizumab for the Treatment of Microsatellite Instability-High Solid Tumors , 2019, Clinical Cancer Research.

[29]  F. Hodi,et al.  Subsets of exhausted CD8+ T cells differentially mediate tumor control and respond to checkpoint blockade , 2019, Nature Immunology.

[30]  T. Powles,et al.  Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal‐Cell Carcinoma , 2019, The New England journal of medicine.

[31]  R. Motzer,et al.  Avelumab plus Axitinib versus Sunitinib for Advanced Renal‐Cell Carcinoma , 2019, The New England journal of medicine.

[32]  T. Chan,et al.  The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy , 2019, Nature Reviews Cancer.

[33]  S. Jalkanen,et al.  Immunotherapeutic Blockade of Macrophage Clever-1 Reactivates the CD8+ T-cell Response against Immunosuppressive Tumors , 2019, Clinical Cancer Research.

[34]  Hongwei Wang,et al.  Tumoral EHF predicts the efficacy of anti-PD1 therapy in pancreatic ductal adenocarcinoma , 2019, The Journal of experimental medicine.

[35]  J. Lunceford,et al.  T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028. , 2019, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[36]  J. Madore,et al.  Distinct Immune Cell Populations Define Response to Anti-PD-1 Monotherapy and Anti-PD-1/Anti-CTLA-4 Combined Therapy. , 2019, Cancer cell.

[37]  Aaron J. Storey,et al.  Loss of E-Cadherin Inhibits CD103 Antitumor Activity and Reduces Checkpoint Blockade Responsiveness in Melanoma. , 2019, Cancer research.

[38]  P. Catalano,et al.  irRECIST for the Evaluation of Candidate Biomarkers of Response to Nivolumab in Metastatic Clear Cell Renal Cell Carcinoma: Analysis of a Phase II Prospective Clinical Trial , 2019, Clinical Cancer Research.

[39]  Lingli Chen,et al.  Tumour-associated macrophages-derived CXCL8 determines immune evasion through autonomous PD-L1 expression in gastric cancer , 2019, Gut.

[40]  S. Ha,et al.  The Ratio of Peripheral Regulatory T Cells to Lox-1+ Polymorphonuclear Myeloid-derived Suppressor Cells Predicts the Early Response to Anti-PD-1 Therapy in Patients with Non-Small Cell Lung Cancer. , 2019, American journal of respiratory and critical care medicine.

[41]  C. Brennan,et al.  Tumor mutational load predicts survival after immunotherapy across multiple cancer types , 2019, Nature Genetics.

[42]  J. Luke,et al.  WNT/β-catenin Pathway Activation Correlates with Immune Exclusion across Human Cancers , 2019, Clinical Cancer Research.

[43]  Daniel Zelterman,et al.  Multiplex Quantitative Analysis of Tumor-Infiltrating Lymphocytes and Immunotherapy Outcome in Metastatic Melanoma , 2019, Clinical Cancer Research.

[44]  J. Galon,et al.  Approaches to treat immune hot, altered and cold tumours with combination immunotherapies , 2019, Nature Reviews Drug Discovery.

[45]  Aviv Regev,et al.  Checkpoint Blockade Immunotherapy Induces Dynamic Changes in PD‐1−CD8+ Tumor‐Infiltrating T Cells , 2019, Immunity.

[46]  D. Thommen.  The First Shall (Be) Last: Understanding Durable T Cell Responses in Immunotherapy. , 2019, Immunity.

[47]  Daniel E. Speiser,et al.  Intratumoral Tcf1+PD‐1+CD8+ T Cells with Stem‐like Properties Promote Tumor Control in Response to Vaccination and Checkpoint Blockade Immunotherapy , 2019, Immunity.

[48]  J. Friedman,et al.  Semaphorin4D Inhibition Improves Response to Immune-Checkpoint Blockade via Attenuation of MDSC Recruitment and Function , 2018, Cancer Immunology Research.

[49]  Aleksey K. Molodtsov,et al.  Tissue Resident CD8 Memory T Cell Responses in Cancer and Autoimmunity , 2018, Front. Immunol..

[50]  L. Zitvogel,et al.  PD-Loma: a cancer entity with a shared sensitivity to the PD-1/PD-L1 pathway blockade , 2018, British Journal of Cancer.

[51]  C. Ager,et al.  Targeted hypoxia reduction restores T cell infiltration and sensitizes prostate cancer to immunotherapy , 2018, The Journal of clinical investigation.

[52]  J. Lunceford,et al.  Pan-tumor genomic biomarkers for PD-1 checkpoint blockade–based immunotherapy , 2018, Science.

[53]  Ludmila V. Danilova,et al.  Multidimensional, quantitative assessment of PD-1/PD-L1 expression in patients with Merkel cell carcinoma and association with response to pembrolizumab , 2018, Journal of Immunotherapy for Cancer.

[54]  E. Van Cutsem,et al.  Durable clinical benefit with nivolumab (NIVO) plus low-dose ipilimumab (IPI) as first-line therapy in microsatellite instability-high/mismatch repair deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC). , 2018, Annals of oncology : official journal of the European Society for Medical Oncology.

[55]  P. Romero,et al.  Tumor Resident Memory T Cells: New Players in Immune Surveillance and Therapy , 2018, Front. Immunol..

[56]  E. Tartour,et al.  Resident memory T cells, critical components in tumor immunology , 2018, Journal of Immunotherapy for Cancer.

[57]  G. Freeman,et al.  Signatures of T cell dysfunction and exclusion predict cancer immunotherapy response , 2018, Nature Medicine.

[58]  E. Tartour,et al.  Targeting Resident Memory T Cells for Cancer Immunotherapy , 2018, Front. Immunol..

[59]  Eytan Ruppin,et al.  Robust prediction of response to immune checkpoint blockade therapy in metastatic melanoma , 2018, Nature Medicine.

[60]  S. Karam,et al.  Resistance to Radiotherapy and PD-L1 Blockade Is Mediated by TIM-3 Upregulation and Regulatory T-Cell Infiltration , 2018, Clinical Cancer Research.

[61]  K. Dhodapkar.  Role of Tissue-Resident Memory in Intra-Tumor Heterogeneity and Response to Immune Checkpoint Blockade , 2018, Front. Immunol..

[62]  B. Fox,et al.  Co-expression of CD39 and CD103 identifies tumor-reactive CD8 T cells in human solid tumors , 2018, Nature Communications.

[63]  K. Leroy,et al.  Abstract 4546: The tumor inflammation signature is predictive of anti-PD1 treatment benefit in the CERTIM pan-cancer cohort , 2018, Clinical Research (Excluding Clinical Trials).

[64]  Chengzhong Ye,et al.  Single-cell profiling of breast cancer T cells reveals a tissue-resident memory subset associated with improved prognosis , 2018, Nature Medicine.

[65]  C. Klein,et al.  A transcriptionally and functionally distinct PD-1+ CD8+ T cell pool with predictive potential in non-small cell lung cancer treated with PD-1 blockade , 2018, Nature Medicine.

[66]  J. Reeves,et al.  Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma , 2018, Nature Medicine.

[67]  G. Getz,et al.  Genomic correlates of response to immune checkpoint blockade in microsatellite-stable solid tumors , 2018, Nature Genetics.

[68]  M. Fehlings,et al.  Bystander CD8+ T cells are abundant and phenotypically distinct in human tumour infiltrates , 2018, Nature.

[69]  Michael Q. Zhang,et al.  Co‐inhibitory Molecule B7 Superfamily Member 1 Expressed by Tumor‐Infiltrating Myeloid Cells Induces Dysfunction of Anti‐tumor CD8+ T Cells , 2018, Immunity.

[70]  S. Novello,et al.  Pembrolizumab plus Chemotherapy in Metastatic Non–Small‐Cell Lung Cancer , 2018, The New England journal of medicine.

[71]  Dai Fukumura,et al.  Functional Anti-TIGIT Antibodies Regulate Development of Autoimmunity and Antitumor Immunity , 2018, The Journal of Immunology.

[72]  N. Bercovici,et al.  Macrophages impede CD8 T cells from reaching tumor cells and limit the efficacy of anti–PD-1 treatment , 2018, Proceedings of the National Academy of Sciences.

[73]  S. Niclou,et al.  Dual PD1/LAG3 immune checkpoint blockade limits tumor development in a murine model of chronic lymphocytic leukemia. , 2018, Blood.

[74]  W. Xue,et al.  Metformin-Induced Reduction of CD39 and CD73 Blocks Myeloid-Derived Suppressor Cell Activity in Patients with Ovarian Cancer. , 2018, Cancer research.

[75]  J. Madore,et al.  CD103+ Tumor-Resident CD8+ T Cells Are Associated with Improved Survival in Immunotherapy-Naïve Melanoma Patients and Expand Significantly During Anti–PD-1 Treatment , 2018, Clinical Cancer Research.

[76]  Bohuslav Melichar,et al.  Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal‐Cell Carcinoma , 2018, The New England journal of medicine.

[77]  Zhihui Liang,et al.  CD103+CD8+ T lymphocytes in non-small cell lung cancer are phenotypically and functionally primed to respond to PD-1 blockade. , 2018, Cellular immunology.

[78]  L. Macconaill,et al.  Frameshift events predict anti-PD-1/L1 response in head and neck cancer. , 2018, JCI insight.

[79]  Camille Stephan-Otto Attolini,et al.  TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis , 2018, Nature.

[80]  Edmond Sabo,et al.  The role of tumor-infiltrating lymphocytes (TILs) as a predictive biomarker of response to anti-PD1 therapy in patients with metastatic non-small cell lung cancer or metastatic melanoma , 2018, Medical Oncology.

[81]  R. Bourgon,et al.  TGF-β attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells , 2018, Nature.

[82]  P. Rochaix,et al.  TNFα blockade overcomes resistance to anti-PD-1 in experimental melanoma , 2017, Nature Communications.

[83]  E. Jaffee,et al.  Tumor Mutational Burden and Response Rate to PD-1 Inhibition. , 2017, The New England journal of medicine.

[84]  Jason B. Williams,et al.  Intratumoral CD8+ T-cell Apoptosis Is a Major Component of T-cell Dysfunction and Impedes Antitumor Immunity , 2017, Cancer Immunology Research.

[85]  Yufeng Shen,et al.  Human Tissue-Resident Memory T Cells Are Defined by Core Transcriptional and Functional Signatures in Lymphoid and Mucosal Sites. , 2017, Cell reports.

[86]  Dana Pe’er,et al.  Distinct Cellular Mechanisms Underlie Anti-CTLA-4 and Anti-PD-1 Checkpoint Blockade , 2017, Cell.

[87]  Peter Schmid,et al.  LBA13Relationship between tumor infiltrating lymphocyte (TIL) levels and response to pembrolizumab (pembro) in metastatic triple-negative breast cancer (mTNBC): Results from KEYNOTE-086 , 2017 .

[88]  E. Tartour,et al.  Tissue-resident memory T cells play a key role in the efficacy of cancer vaccines , 2017, Oncoimmunology.

[89]  R. Weinberg,et al.  Predicting the response to CTLA-4 blockade by longitudinal noninvasive monitoring of CD8 T cells , 2017, The Journal of experimental medicine.

[90]  L. Del Valle,et al.  Exogenous lipid uptake induces metabolic and functional reprogramming of tumor-associated myeloid-derived suppressor cells , 2017, Oncoimmunology.

[91]  J. Lunceford,et al.  IFN-&ggr;–related mRNA profile predicts clinical response to PD-1 blockade , 2017, The Journal of clinical investigation.

[92]  E. Tartour,et al.  Mechanisms of action and rationale for the use of checkpoint inhibitors in cancer , 2017, ESMO Open.

[93]  P. Hegde,et al.  Abstract CT081: Molecular correlates of differential response to Atezolizumab +/- Bevacizumab vs Sunitnib in a Phase II study in untreated metastatic renal cell carcinoma (RCC) patients , 2017 .

[94]  F. Hodi,et al.  Monitoring immune-checkpoint blockade: response evaluation and biomarker development , 2017, Nature Reviews Clinical Oncology.

[95]  E. King,et al.  Tissue-resident memory features are linked to the magnitude of cytotoxic T cell responses in human lung cancer , 2017, Nature Immunology.

[96]  Leo Swadling,et al.  IL-2high tissue-resident T cells in the human liver: Sentinels for hepatotropic infection , 2017, The Journal of experimental medicine.

[97]  P. Ascierto,et al.  Initial efficacy of anti-lymphocyte activation gene-3 (anti–LAG-3; BMS-986016) in combination with nivolumab (nivo) in pts with melanoma (MEL) previously treated with anti–PD-1/PD-L1 therapy. , 2017 .

[98]  E. Tartour,et al.  Induction of resident memory T cells enhances the efficacy of cancer vaccine , 2017, Nature Communications.

[99]  Nicolai J. Birkbak,et al.  Tracking the Evolution of Non‐Small‐Cell Lung Cancer , 2017, The New England journal of medicine.

[100]  Jedd D. Wolchok,et al.  T-cell invigoration to tumour burden ratio associated with anti-PD-1 response , 2017, Nature.

[101]  E. Tartour,et al.  Tim-3 Expression on Tumor-Infiltrating PD-1+CD8+ T Cells Correlates with Poor Clinical Outcome in Renal Cell Carcinoma. , 2017, Cancer research.

[102]  S. Chouaib,et al.  Hypoxic stress: obstacles and opportunities for innovative immunotherapy of cancer , 2017, Oncogene.

[103]  J. Sosman,et al.  Genomic and Transcriptomic Features of Response to Anti-PD-1 Therapy in Metastatic Melanoma , 2017, Cell.

[104]  R. Ferris,et al.  Adaptive resistance to anti-PD1 therapy by Tim-3 upregulation is mediated by the PI3K-Akt pathway in head and neck cancer , 2017, Oncoimmunology.

[105]  S. Ariyan,et al.  Interlesional diversity of T cell receptors in melanoma with immune checkpoints enriched in tissue-resident memory T cells. , 2016, JCI insight.

[106]  S. Berger,et al.  Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade , 2016, Science.

[107]  H. Clevers,et al.  Programs for the persistence, vigilance and control of human CD8+ lung-resident memory T cells , 2016, Nature Immunology.

[108]  J. Wargo,et al.  Loss of IFN-γ Pathway Genes in Tumor Cells as a Mechanism of Resistance to Anti-CTLA-4 Therapy , 2016, Cell.

[109]  P. Hegde,et al.  Atezolizumab, an Anti-Programmed Death-Ligand 1 Antibody, in Metastatic Renal Cell Carcinoma: Long-Term Safety, Clinical Activity, and Immune Correlates From a Phase Ia Study. , 2016, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[110]  L. Nardo,et al.  Tumor immune profiling predicts response to anti-PD-1 therapy in human melanoma. , 2016, The Journal of clinical investigation.

[111]  Ludmila V. Danilova,et al.  The Intratumoral Balance between Metabolic and Immunologic Gene Expression Is Associated with Anti–PD-1 Response in Patients with Renal Cell Carcinoma , 2016, Cancer Immunology Research.

[112]  L. Chin,et al.  Analysis of Immune Signatures in Longitudinal Tumor Samples Yields Insight into Biomarkers of Response and Mechanisms of Resistance to Immune Checkpoint Blockade. , 2016, Cancer discovery.

[113]  T. Graeber,et al.  Mutations Associated with Acquired Resistance to PD-1 Blockade in Melanoma. , 2016, The New England journal of medicine.

[114]  V. Kuchroo,et al.  Lag-3, Tim-3, and TIGIT: Co-inhibitory Receptors with Specialized Functions in Immune Regulation. , 2016, Immunity.

[115]  R. Bourgon,et al.  Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial , 2016, The Lancet.

[116]  Keunchil Park,et al.  Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial , 2016, The Lancet.

[117]  Drew M. Pardoll,et al.  PD-1 Blockade with Pembrolizumab in Advanced Merkel-Cell Carcinoma. , 2016, The New England journal of medicine.

[118]  P. Hegde,et al.  The Where, the When, and the How of Immune Monitoring for Cancer Immunotherapies in the Era of Checkpoint Inhibition , 2016, Clinical Cancer Research.

[119]  Jing Wang,et al.  STK11/LKB1 Deficiency Promotes Neutrophil Recruitment and Proinflammatory Cytokine Production to Suppress T-cell Activity in the Lung Tumor Microenvironment. , 2016, Cancer research.

[120]  Shohei Koyama,et al.  Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints , 2016, Nature Communications.

[121]  J. McQuade,et al.  Loss of PTEN Promotes Resistance to T Cell-Mediated Immunotherapy. , 2016, Cancer discovery.

[122]  C. Klein,et al.  Progression of Lung Cancer Is Associated with Increased Dysfunction of T Cells Defined by Coexpression of Multiple Inhibitory Receptors , 2015, Cancer Immunology Research.

[123]  J. Lunceford,et al.  Association of response to programmed death receptor 1 (PD-1) blockade with pembrolizumab (MK-3475) with an interferon-inflammatory immune gene signature. , 2015 .

[124]  J. Lunceford,et al.  Inflamed-phenotype gene expression signatures to predict benefit from the anti-PD-1 antibody pembrolizumab in PD-L1+ head and neck cancer patients. , 2015 .

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

[126]  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.

[127]  P. Sharma,et al.  The future of immune checkpoint therapy , 2015, Science.

[128]  Yuzhen Wang,et al.  MicroRNA‐155 deficiency enhances the recruitment and functions of myeloid‐derived suppressor cells in tumor microenvironment and promotes solid tumor growth , 2015, International journal of cancer.

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

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

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

[132]  N. Rouas-Freiss,et al.  In vivo evidence that secretion of HLA‐G by immunogenic tumor cells allows their evasion from immunosurveillance , 2014, International journal of cancer.

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

[134]  P. Dessen,et al.  PD-L1 is a novel direct target of HIF-1α, and its blockade under hypoxia enhanced MDSC-mediated T cell activation , 2014, The Journal of experimental medicine.

[135]  Scott N. Mueller,et al.  The developmental pathway for CD103+CD8+ tissue-resident memory T cells of skin , 2013, Nature Immunology.

[136]  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.

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

[138]  Matteo Bellone,et al.  Ways to Enhance Lymphocyte Trafficking into Tumors and Fitness of Tumor Infiltrating Lymphocytes , 2013, Front. Oncol..

[139]  L. Zitvogel,et al.  Comprehensive analysis of current approaches to inhibit regulatory T cells in cancer , 2012, Oncoimmunology.

[140]  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.

[141]  Pierre Validire,et al.  Matrix architecture defines the preferential localization and migration of T cells into the stroma of human lung tumors. , 2012, The Journal of clinical investigation.

[142]  L. Lazzarato,et al.  Chemokine nitration prevents intratumoral infiltration of antigen-specific T cells , 2011, The Journal of experimental medicine.

[143]  Lin Zhang,et al.  Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and Treg cells , 2011, Nature.

[144]  E. Tartour,et al.  Angiogenesis and immunity: a bidirectional link potentially relevant for the monitoring of antiangiogenic therapy and the development of novel therapeutic combination with immunotherapy , 2011, Cancer and Metastasis Reviews.

[145]  James O. Jones,et al.  Suppression of Antitumor Immunity by Stromal Cells Expressing Fibroblast Activation Protein–α , 2010, Science.

[146]  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.

[147]  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.

[148]  M. Tretiakova,et al.  Chemokine expression in melanoma metastases associated with CD8+ T-cell recruitment. , 2009, Cancer research.

[149]  G. Keren,et al.  Hypoxia controls CD4+CD25+ regulatory T‐cell homeostasis via hypoxia‐inducible factor‐1α , 2008, European journal of immunology.

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

[151]  D. Munn,et al.  Indoleamine 2,3-dioxygenase and tumor-induced tolerance. , 2007, The Journal of clinical investigation.

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

[153]  J. Brayer,et al.  Arginase I Production in the Tumor Microenvironment by Mature Myeloid Cells Inhibits T-Cell Receptor Expression and Antigen-Specific T-Cell Responses , 2004, Cancer Research.

[154]  J. Tschopp,et al.  Melanoma Cell Expression of Fas(Apo-1/CD95) Ligand: Implications for Tumor Immune Escape , 1996, Science.

[155]  Vanessa M. Hubbard-Lucey,et al.  Comprehensive analysis of the clinical immuno-oncology landscape , 2018, Annals of oncology : official journal of the European Society for Medical Oncology.

[156]  A. Nebreda,et al.  TGF ‐ beta drives immune evasion in genetically reconstituted colon cancer metastasis , 2018 .

[157]  Jason B. Williams,et al.  Cancer Immunotherapy Targets Based on Understanding the T Cell-Inflamed Versus Non-T Cell-Inflamed Tumor Microenvironment. , 2017, Advances in experimental medicine and biology.

[158]  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 .