PD-1 and PD-L1 in cancer immunotherapy: clinical implications and future considerations

ABSTRACT Programmed death-1 (PD-1) is a cell surface receptor that functions as a T cell checkpoint and plays a central role in regulating T cell exhaustion. Binding of PD-1 to its ligand, programmed death-ligand 1 (PD-L1), activates downstream signaling pathways and inhibits T cell activation. Moreover abnormally high PD-L1 expression on tumor cells and antigen-presenting cells in the tumor microenvironment mediates tumor immune escape, and the development of anti-PD-1/PD-L1 antibodies has recently become a hot topic in cancer immunotherapy. Here, we review the structure of PD-1 and PD-L1, the function of the PD-1/PD-L1 signaling pathway, the application of PD-1 or PD-L1 monoclonal antibodies and future directions for anti-PD-1/PD-L1 antibodies with combination therapies. Cancer immunotherapy using PD-1/PD-L1 immune checkpoint blockade may require more studies, and this approach may be curative for patients with many types of cancer in the future.

[1]  T. Honjo,et al.  Induced expression of PD‐1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. , 1992, The EMBO journal.

[2]  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.

[3]  G. Freeman,et al.  PD-L2 is a second ligand for PD-1 and inhibits T cell activation , 2001, Nature Immunology.

[4]  G. Freeman,et al.  Expression and Regulation of the PD‐L1 Immunoinhibitory Molecule on Microvascular Endothelial Cells , 2002, Microcirculation.

[5]  C. June,et al.  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 Activation1 , 2004, The Journal of Immunology.

[6]  M. Weller,et al.  Interferon-β enhances monocyte and dendritic cell expression of B7-H1 (PD-L1), a strong inhibitor of autologous T-cell activation: relevance for the immune modulatory effect in multiple sclerosis , 2004, Journal of Neuroimmunology.

[7]  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.

[8]  G. Freeman,et al.  PD-1 and its ligands in tolerance and immunity. , 2008, Annual review of immunology.

[9]  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.

[10]  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.

[11]  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.

[12]  J. Allison,et al.  Combination CTLA-4 Blockade and 4-1BB Activation Enhances Tumor Rejection by Increasing T-Cell Infiltration, Proliferation, and Cytokine Production , 2011, PloS one.

[13]  Manuela M. Santos,et al.  Impact of hemochromatosis gene (HFE) mutations on epithelial ovarian cancer risk and prognosis , 2011, International journal of cancer.

[14]  P. Tien,et al.  PD‐1 and PD‐L1 upregulation promotes CD8+ T‐cell apoptosis and postoperative recurrence in hepatocellular carcinoma patients , 2011, International journal of cancer.

[15]  V. Boussiotis,et al.  PD-1 inhibits T cell proliferation by upregulating p27 and p15 and suppressing Cdc25A , 2012, Cell cycle.

[16]  E. Flaño,et al.  Local Blockade of Epithelial PDL-1 in the Airways Enhances T Cell Function and Viral Clearance during Influenza Virus Infection , 2013, Journal of Virology.

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

[18]  D. Rimm,et al.  Sarcomatoid Lung Carcinomas Show High Levels of Programmed Death Ligand-1 (PD-L1) , 2013, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[19]  R. Noelle,et al.  VISTA Regulates the Development of Protective Antitumor Immunity. , 2014, Cancer research.

[20]  K. Tarte,et al.  High level of soluble programmed cell death ligand 1 in blood impacts overall survival in aggressive diffuse large B-Cell lymphoma: results from a French multicenter clinical trial , 2014, Leukemia.

[21]  R. Ahmed,et al.  Blimp-1 represses CD8 T cell expression of PD-1 using a feed-forward transcriptional circuit during acute viral infection , 2014, The Journal of experimental medicine.

[22]  M. Shipp,et al.  PD-1 Blockade with the Monoclonal Antibody Pembrolizumab (MK-3475) in Patients with Classical Hodgkin Lymphoma after Brentuximab Vedotin Failure: Preliminary Results from a Phase 1b Study (KEYNOTE-013) , 2014 .

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

[24]  Lijuan Huang,et al.  The PD-1/PD-Ls pathway and autoimmune diseases. , 2014, Cellular immunology.

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

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

[27]  R. Mace,et al.  Sex equality can explain the unique social structure of hunter-gatherer bands , 2015, Science.

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

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

[30]  Razelle Kurzrock,et al.  PD-L1 Expression as a Predictive Biomarker in Cancer Immunotherapy , 2015, Molecular Cancer Therapeutics.

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

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

[33]  E. Furth,et al.  Induction of T-cell Immunity Overcomes Complete Resistance to PD-1 and CTLA-4 Blockade and Improves Survival in Pancreatic Carcinoma , 2015, Cancer Immunology Research.

[34]  A. Waage,et al.  PDL1 Expression on Plasma and Dendritic Cells in Myeloma Bone Marrow Suggests Benefit of Targeted anti PD1-PDL1 Therapy , 2015, PloS one.

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

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

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

[38]  E. Wherry,et al.  Overcoming T cell exhaustion in infection and cancer. , 2015, Trends in immunology.

[39]  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.

[40]  J. Lee,et al.  The expression profiles and regulation of PD-L1 in tumor-induced myeloid-derived suppressor cells , 2016, Oncoimmunology.

[41]  J. Wolchok,et al.  Association of Pembrolizumab With Tumor Response and Survival Among Patients With Advanced Melanoma. , 2016, JAMA.

[42]  J. Taube,et al.  Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy , 2016, Nature Reviews Cancer.

[43]  I. Lowy,et al.  Responses of metastatic basal cell and cutaneous squamous cell carcinomas to anti-PD1 monoclonal antibody REGN2810 , 2016, Journal of Immunotherapy for Cancer.

[44]  A. Mansfield,et al.  Temporal and spatial discordance of programmed cell death-ligand 1 expression and lymphocyte tumor infiltration between paired primary lesions and brain metastases in lung cancer , 2016, Annals of oncology : official journal of the European Society for Medical Oncology.

[45]  [Atezolizumab (Tecentriq®): Activity, indication and modality of use in advanced or metastatic urinary bladder carcinoma]. , 2017, Bulletin du cancer.

[46]  M. Rollins,et al.  CD80 Expressed by CD8+ T Cells Contributes to PD-L1-Induced Apoptosis of Activated CD8+ T Cells , 2017, Journal of immunology research.

[47]  Charles H. Yoon,et al.  An immunogenic personal neoantigen vaccine for patients with melanoma , 2017, Nature.

[48]  R. Pierce,et al.  PD-1 Expression in Head and Neck Squamous Cell Carcinomas Derives Primarily from Functionally Anergic CD4+ TILs in the Presence of PD-L1+ TAMs. , 2017, Cancer research.

[49]  C. Massard,et al.  Atézolizumab (Tecentriq®) : activité, indication et modalités d’utilisation dans les carcinomes urothéliaux localement avancés ou métastatiques , 2017 .

[50]  P. Ascierto,et al.  Correlation between previous treatment with BRAF inhibitors and clinical response to pembrolizumab in patients with advanced melanoma , 2017, Oncoimmunology.

[51]  M. Kudo,et al.  Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial , 2017, The Lancet.

[52]  P. Dahm,et al.  Nivolumab for adult individuals with Hodgkin lymphoma (an exemplar rapid review using RobotReviewer) , 2017 .

[53]  Daniel M. Corey,et al.  PD-1 expression by tumor-associated macrophages inhibits phagocytosis and tumor immunity , 2017, Nature.

[54]  Tarek Mekhail,et al.  Durvalumab after Chemoradiotherapy in Stage III Non–Small‐Cell Lung Cancer , 2017, The New England journal of medicine.

[55]  Lynley A. Wallis,et al.  Human occupation of northern Australia by 65,000 years ago , 2017, Nature.

[56]  Atezolizumab Extends Survival for Breast Cancer. , 2017, Cancer discovery.

[57]  Ludmila V. Danilova,et al.  Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade , 2017, Science.

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

[59]  K. Kelly,et al.  Avelumab for patients with previously treated metastatic or recurrent non-small-cell lung cancer (JAVELIN Solid Tumor): dose-expansion cohort of a multicentre, open-label, phase 1b trial. , 2017, The Lancet. Oncology.

[60]  J. Lunceford,et al.  PD-L2 Expression in Human Tumors: Relevance to Anti-PD-1 Therapy in Cancer , 2017, Clinical Cancer Research.

[61]  Christopher M. Jackson,et al.  TIGIT and PD-1 dual checkpoint blockade enhances antitumor immunity and survival in GBM , 2018, Oncoimmunology.

[62]  H. Mistry,et al.  Pembrolizumab for Previously Treated Advanced or Metastatic Urothelial Cancer: An Evidence Review Group Perspective of a NICE Single Technology Appraisal , 2018, PharmacoEconomics.

[63]  Laurence Zitvogel,et al.  Gut microbiome influences efficacy of PD-1–based immunotherapy against epithelial tumors , 2018, Science.

[64]  Y. Koh,et al.  Correlation between immune-related adverse events and efficacy in non-small cell lung cancer treated with nivolumab. , 2018, Lung cancer.

[65]  S. Paydaş,et al.  PD-1 and PD-L1 expression in thymic epithelial tumours and non-neoplastic thymus , 2018, Journal of Clinical Pathology.

[66]  T. Greten,et al.  Indoleamine 2,3-dioxygenase provides adaptive resistance to immune checkpoint inhibitors in hepatocellular carcinoma , 2018, Cancer Immunology, Immunotherapy.

[67]  P. Chow,et al.  Multidimensional analyses reveal distinct immune microenvironment in hepatitis B virus-related hepatocellular carcinoma , 2018, Gut.

[68]  J. Szustakowski,et al.  Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden , 2018, The New England journal of medicine.

[69]  I. Pastan,et al.  Anti-drug antibodies to LMB-100 are enhanced by mAbs targeting OX40 and CTLA4 but not by mAbs targeting PD1 or PDL-1. , 2018, Cellular immunology.

[70]  G. Prendergast,et al.  Inhibiting IDO pathways to treat cancer: lessons from the ECHO-301 trial and beyond , 2018, Seminars in Immunopathology.

[71]  Lieping Chen,et al.  A Paradigm Shift in Cancer Immunotherapy: From Enhancement to Normalization , 2018, Cell.

[72]  Jedd D. Wolchok,et al.  Cancer immunotherapy using checkpoint blockade , 2018, Science.

[73]  P. Bach,et al.  Financial Conflicts of Interest Among Oncology Clinical Pathway Vendors , 2017, JAMA oncology.

[74]  A. Hauschild,et al.  PD‐1 Blockade with Cemiplimab in Advanced Cutaneous Squamous‐Cell Carcinoma , 2018, The New England journal of medicine.

[75]  I. Braña,et al.  Safety and Efficacy of Durvalumab With or Without Tremelimumab in Patients With PD-L1–Low/Negative Recurrent or Metastatic HNSCC: The Phase 2 CONDOR Randomized Clinical Trial , 2019, JAMA oncology.

[76]  E. Le Chatelier,et al.  Gut microbiome modulates response to anti–PD-1 immunotherapy in melanoma patients , 2018, Science.

[77]  Arun Ahuja,et al.  Genomic Features of Response to Combination Immunotherapy in Patients with Advanced Non-Small-Cell Lung Cancer , 2018, Cancer cell.

[78]  Zhiming Wang,et al.  CLEC1B Expression and PD-L1 Expression Predict Clinical Outcome in Hepatocellular Carcinoma with Tumor Hemorrhage12 , 2018, Translational oncology.

[79]  D. Planchard,et al.  Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC , 2018, The New England journal of medicine.

[80]  Paolo A Ascierto,et al.  Tumor Mutational Burden and Efficacy of Nivolumab Monotherapy and in Combination with Ipilimumab in Small-Cell Lung Cancer. , 2018, Cancer cell.

[81]  P. Dahm,et al.  Nivolumab for adults with Hodgkin's lymphoma (a rapid review using the software RobotReviewer). , 2018, The Cochrane database of systematic reviews.

[82]  N. Rizvi,et al.  Combining chemotherapy with PD‐1 blockade in NSCLC , 2018, Pharmacology & therapeutics.

[83]  Ö. Türeci,et al.  Personalized vaccines for cancer immunotherapy , 2018, Science.

[84]  K. Savage,et al.  Nivolumab for Relapsed/Refractory Classic Hodgkin Lymphoma After Failure of Autologous Hematopoietic Cell Transplantation: Extended Follow-Up of the Multicohort Single-Arm Phase II CheckMate 205 Trial , 2018, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[85]  Y. Bang,et al.  Pembrolizumab in Asia‐Pacific patients with advanced head and neck squamous cell carcinoma: Analyses from KEYNOTE‐012 , 2018, Cancer science.

[86]  Riyue Bao,et al.  The commensal microbiome is associated with anti–PD-1 efficacy in metastatic melanoma patients , 2018, Science.

[87]  J. Grob,et al.  Efficacy and Safety of First-line Avelumab Treatment in Patients With Stage IV Metastatic Merkel Cell Carcinoma: A Preplanned Interim Analysis of a Clinical Trial , 2018, JAMA oncology.

[88]  G. Zhu,et al.  Fibrinogen-like Protein 1 Is a Major Immune Inhibitory Ligand of LAG-3 , 2019, Cell.