Journal Articles

Checkpoint modulation

Cancer immunotherapeutic approaches that target stimulatory or inhibitory immune checkpoint pathways as well as immune related adverse events associated with these therapies

Phase II trial of ipilimumab in melanoma patients with preexisting humoural immune response to NY-ESO-1

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BACKGROUND: Immune checkpoint therapy has dramatically changed treatment options in patients with metastatic melanoma. However, a relevant part of patients still does not respond to treatment. Data regarding the prognostic or predictive significance of preexisting immune responses against tumour antigens are conflicting. Retrospective data suggested a higher clinical benefit of ipilimumab in melanoma patients with preexisting NY-ESO-1-specific immunity. PATIENTS AND METHODS: Twenty-five patients with previously untreated or treated metastatic melanoma and preexisting humoural immune response against NY-ESO-1 received ipilimumab at a dose of 10 mg/kg in week 1, 4, 7, 10 followed by 3-month maintenance treatment for a maximum of 48 weeks. Primary endpoint was the disease control rate (irCR, irPR or irSD) according to immune-related response criteria (irRC). Secondary endpoints included the disease control rate according to RECIST criteria, progression-free survival and overall survival (OS). Humoural and cellular immune responses against NY-ESO-1 were analysed from blood samples. RESULTS: Disease control rate according to irRC was 52%, irPR was observed in 36% of patients. Progression-free survival according to irRC was 7.8 months, according to RECIST criteria it was 2.9 months. Median OS was 22.7 months; the corresponding 1-year survival rate was 66.8%. Treatment-related grade 3 AEs occurred in 36% with no grade 4-5 AEs. No clear association was found between the presence of NY-ESO-1-specific cellular or humoural immune responses and clinical activity. CONCLUSION: Ipilimumab demonstrated clinically relevant activity within this biomarker-defined population. NY-ESO-1 positivity, as a surrogate for a preexisting immune response against tumour antigens, might help identifying patients with a superior outcome from immune checkpoint blockade. CLINICAL TRIAL INFORMATION: NCT01216696.

Author Info: (1) Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, Germany. Electronic address: GeorgMartin.Haag@med.uni-heidelberg.de. (2) Department of Medical Oncology, National Center for

Author Info: (1) Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, Germany. Electronic address: GeorgMartin.Haag@med.uni-heidelberg.de. (2) Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, Germany. (3) Department of Dermatology and National Center for Tumor Diseases, University Hospital Heidelberg, Germany. (4) Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, Germany. (5) Department of Dermatology and National Center for Tumor Diseases, University Hospital Heidelberg, Germany. (6) Department of Dermatology and National Center for Tumor Diseases, University Hospital Heidelberg, Germany. (7) Translational Immunology, National Center for Tumor Diseases, Heidelberg, Germany. (8) Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, Germany. (9) Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, Germany. (10) Translational Immunology, National Center for Tumor Diseases, Heidelberg, Germany. (11) Translational Immunology, National Center for Tumor Diseases, Heidelberg, Germany. (12) Translational Immunology, National Center for Tumor Diseases, Heidelberg, Germany. (13) Institute of Transplant Immunology, IFB-Tx, Hannover Medical School, Hannover, Germany. (14) NCT Trial Center, National Center for Tumor Diseases, Heidelberg, Germany. (15) NCT Trial Center, National Center for Tumor Diseases, Heidelberg, Germany. (16) Translational Immunology, National Center for Tumor Diseases, Heidelberg, Germany; Regensburg Center for Interventional Immunology, University Hospital Regensburg, Germany. (17) Department of Dermatology and National Center for Tumor Diseases, University Hospital Heidelberg, Germany. (18) Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, Germany; Clinical Cooperation Unit "Applied Tumor-Immunity", German Cancer Research Center (DKFZ), Heidelberg, Germany.

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Activation of 4-1BB on liver myeloid cells triggers hepatitis via an interleukin-27 dependent pathway

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PURPOSE: Agonist antibodies targeting the T cell co-stimulatory receptor 4-1BB (CD137) are among the most effective immunotherapeutic agents across pre-clinical cancer models. In the clinic, however, development of these agents has been hampered by dose-limiting liver toxicity. Lack of knowledge of the mechanisms underlying this toxicity has limited the potential to separate 4-1BB agonist driven tumor immunity from hepatotoxicity. EXPERIMENTAL DESIGN: The capacity of 4-1BB agonist antibodies to induce liver toxicity was investigated in immunocompetent mice, with or without co-administration of checkpoint blockade, via 1) measurement of serum transaminase levels, 2) imaging of liver immune infiltrates, and 3) qualitative and quantitative assessment of liver myeloid and T cells via flow cytometry. Knockout mice were used to clarify the contribution of specific cell subsets, cytokines and chemokines. RESULTS: We find that activation of 4-1BB on liver myeloid cells is essential to initiate hepatitis. Once activated, these cells produce interleukin-27 that is required for liver toxicity. CD8 T cells infiltrate the liver in response to this myeloid activation and mediate tissue damage, triggering transaminase elevation. FoxP3+ regulatory T cells limit liver damage, and their removal dramatically exacerbates 4-1BB agonist-induced hepatitis. Co-administration of CTLA-4 blockade ameliorates transaminase elevation, whereas PD-1 blockade exacerbates it. Loss of the chemokine receptor CCR2 blocks 4-1BB agonist hepatitis without diminishing tumor-specific immunity against B16 melanoma. CONCLUSIONS: 4-1BB agonist antibodies trigger hepatitis via activation and expansion of interleukin-27-producing liver Kupffer cells and monocytes. Co-administration of CTLA-4 and/or CCR2 blockade may minimize hepatitis, but yield equal or greater antitumor immunity.

Author Info: (1) Immunology, University of Texas MD Anderson Cancer Center. (2) Immunology, University of Texas MD Anderson Cancer Center. (3) Immunology Program, University of Texas Graduate

Author Info: (1) Immunology, University of Texas MD Anderson Cancer Center. (2) Immunology, University of Texas MD Anderson Cancer Center. (3) Immunology Program, University of Texas Graduate School of Biomedical Sciences at Houston. (4) Immunology, The University of Texas MD Anderson Cancer Center. (5) Immunology, The University of Texas MD Anderson Cancer Center. (6) Immunology, The University of Texas MD Anderson Cancer Center. (7) Immunology, The University of Texas MD Anderson Cancer Center. (8) Cancer Medicine, University of Texas MD Anderson Cancer Center. (9) Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center. (10) Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center. (11) Immunology Program, University of Texas Graduate School of Biomedical Sciences at Houston mcurran@mdanderson.org.

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Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma

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Immune checkpoint inhibitors targeting the programmed cell death-1 receptor (PD-1) improve survival in a subset of patients with clear cell renal cell carcinoma (ccRCC). To identify genomic alterations in ccRCC that correlate with response to anti-PD-1 monotherapy, we performed whole exome sequencing of metastatic ccRCC from 35 patients. We found that clinical benefit was associated with loss-of-function mutations in the PBRM1 gene (p=0.012), which encodes a subunit of a SWI/SNF chromatin remodeling complex (the PBAF subtype). We confirmed this finding in an independent validation cohort of 63 ccRCC patients treated with PD-(L)1 blockade therapy alone or in combination with anti-CTLA-4 therapies (p=0.0071). Gene expression analysis of PBAF-deficient ccRCC cell lines and PBRM1-deficient tumors revealed altered transcriptional output in JAK/STAT, hypoxia, and immune signaling pathways. PBRM1 loss in ccRCC may alter global tumor cell expression profiles to influence responsiveness to immune checkpoint therapy.

Author Info: (1) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA 02142

Author Info: (1) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA 02142, USA. (2) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA 02142, USA. (3) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (4) Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Weill Cornell Medical College, New York, NY 10065, USA. (5) Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (6) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (7) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (8) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (9) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA 02142, USA. (10) Bristol-Myers Squibb, New York, NY 10154, USA. (11) Bristol-Myers Squibb, New York, NY 10154, USA. (12) Bristol-Myers Squibb, New York, NY 10154, USA. (13) Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA 02142, USA. (14) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA 02142, USA. (15) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (16) Columbia University Medical Center, New York, NY 10032, USA. (17) James Buchanan Brady Urological Institute and Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. (18) James Buchanan Brady Urological Institute and Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. (19) Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (20) Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Weill Cornell Medical College, New York, NY 10065, USA. (21) Mayo Clinic, Scottsdale, AZ 85259, USA. (22) Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Weill Cornell Medical College, New York, NY 10065, USA. (23) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (24) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Howard Hughes Medical Institute, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (25) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. eliezerm_vanallen@dfci.harvard.edu toni_choueiri@dfci.harvard.edu. (26) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. eliezerm_vanallen@dfci.harvard.edu toni_choueiri@dfci.harvard.edu. Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA 02142, USA.

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A major chromatin regulator determines resistance of tumor cells to T cell-mediated killing

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Many human cancers are resistant to immunotherapy for reasons that are poorly understood. We used a genome-scale CRISPR/Cas9 screen to identify mechanisms of tumor cell resistance to killing by cytotoxic T cells, the central effectors of anti-tumor immunity. Inactivation of >100 genes sensitized mouse B16F10 melanoma cells to killing by T cells, including Pbrm1, Arid2 and Brd7, which encode components of the PBAF form of the SWI/SNF chromatin remodeling complex. Loss of PBAF function increased tumor cell sensitivity to interferon-gamma, resulting in enhanced secretion of chemokines that recruit effector T cells. Treatment-resistant tumors became responsive to immunotherapy when Pbrm1 was inactivated. In many human cancers, expression of PBRM1 and ARID2 inversely correlated with expression of T cell cytotoxicity genes, and Pbrm1-deficient murine melanomas were more strongly infiltrated by cytotoxic T cells.

Author Info: (1) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (2) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston

Author Info: (1) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (2) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (3) Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (4) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (5) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (6) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (7) Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (8) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (9) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (10) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (11) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (12) Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (13) Genetic Perturbation Platform, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. (14) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (15) Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. kai_wucherpfennig@dfci.harvard.edu xsliu@jimmy.harvard.edu. (16) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. kai_wucherpfennig@dfci.harvard.edu xsliu@jimmy.harvard.edu. Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.

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Immunotherapy for Non-small-cell Lung Cancer: Current Status and Future Obstacles

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Lung cancer is one of the leading causes of death worldwide. There are 2 major subtypes of lung cancer, non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). Studies show that NSCLC is the more prevalent type of lung cancer that accounts for approximately 80%-85% of cases. Although, various treatment methods, such as chemotherapy, surgery, and radiation therapy have been used to treat lung cancer patients, there is an emergent need to develop more effective approaches to deal with advanced stages of tumors. Recently, immunotherapy has emerged as a new approach to combat with such tumors. The development and success of programmed cell death 1 (PD-1)/program death-ligand 1 (PD-L1) inhibitors and cytotoxic T-lymphocyte antigen 4 (CTLA-4) blockades in treating metastatic cancers opens a new pavement for the future research. The current mini review discusses the significance of immune checkpoint inhibitors in promoting the death of tumor cells. Additionally, this review also addresses the importance of tumor-specific antigens (neoantigens) in the development of cancer vaccines and major challenges associated with this therapy. Immunotherapy can be a promising approach to treat NSCLC because it stimulates host's own immune system to recognize cancer cells. Therefore, future research should focus on the development of new methodologies to identify novel checkpoint inhibitors and potential neoantigens.

Author Info: (1) Arthur G. James Cancer Hospital Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.

Author Info: (1) Arthur G. James Cancer Hospital Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.

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Pembrolizumab in advanced pretreated small cell lung cancer patients with PD-L1 expression: data from the KEYNOTE-028 trial: a reason for hope

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Small cell lung cancer (SCLC) is an aggressive subtype of lung cancer, representing around 15% of all lung cancer cases. SCLC is characterized by neuroendocrine pathological features, strong association with tobacco exposure, rapid widespread, high mutational rates and no oncogenic drivers (1). At diagnosis, around 70% of cases present with extensive disease (ED-SCLC). Platinum-etoposide doublet is the standard of care, offering response rates of 70_80%. However, despite this initial significant chemosensitivity, progression of the disease will occur after completion of chemotherapy, with median progression-free survival (PFS) of only 2_3 months. In the refractory setting, topotecan offers modest benefit, with response rates of 10% to 20%, and significant toxicity. Consequently, the overall prognosis for patients with ED-SCLC is poor, with median overall survival (OS) of 8_13 months and 5-year OS rate of 1_2% (2)

Author Info: (1) Medical Oncology Department, Vall d'Hebron Hospital and Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. (2) Medical Oncology Department, Vall d'Hebron Hospital and Vall

Author Info: (1) Medical Oncology Department, Vall d'Hebron Hospital and Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. (2) Medical Oncology Department, Vall d'Hebron Hospital and Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.

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The reproducibility of PD-L1 scoring in lung cancer: can the pathologists do better

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In the era of personalized medicine, the selection of advanced stages non-small cell lung cancer (NSCLC) patients for targeted treatments requires development, validation and continuous quality assessments of a wide array of laboratory assays, including both conventional and developing methodologies. While high throughput molecular testing approaches, to extensively assess genomic biomarkers of current and potential clinical value, are fascinating innovations in the field of modern oncology, traditional morpho-molecular methodologies such as fluorescent in situ hybridisation and immunohistochemical (IHC) techniques are still precious in the clinic to guide therapeutic interventions (1). This holds even more true, when considering the recent requirements to evaluate in NSCLC cells the checkpoint inhibitor programmed cell death ligand 1 (PD-L1) protein expression. Different primary antibody clones, raised against different epitopes (parts) of the PD-L1, are available (2). Each clone is linked to a specific treatment: clone 28-8 (Dako, Glostrup, Denmark) for nivolumab, 22C3 (Dako) for pembrolizumab, SP142 (Ventana, Tucson, AZ, USA) for atezolizumab and SP263 (Ventana) for durvalumab. Different clinical trial performed its own PD-L1 immunohistochemistry assay as a prepackaged kit of reagents running on company-specific staining platforms according to the manufacturersinstructions either on the Dako Link AS-48 (no longer available commercially) or on the Ventana Benchmark autostainer systems, adopting custom scoring-criteria for each assay (2)

Author Info: (1) Department of Public Health, University of Naples Federico II, Naples, Italy. (2) Division of Medical Oncology, "S.G. Moscati" Hospital, Avellino, Italy.

Author Info: (1) Department of Public Health, University of Naples Federico II, Naples, Italy. (2) Division of Medical Oncology, "S.G. Moscati" Hospital, Avellino, Italy.

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Small-cell lung cancer in the era of immunotherapy

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Small-cell lung cancer represents about 13_15% of all lung cancers, accounting for more than 275,000 new cases worldwide every year (1). It is a poorly differentiated, high-grade carcinoma thought to originate from neuroendocrine-cell precursors within the bronchi. Small-cell lung cancer is strongly associated with heavy tobacco exposure and typically has a high mutation burden. To date, no targeted therapy has been proven to be effective in small cell lung cancer patients (1,2). Small-cell lung cancer has a high incidence of early metastasis. At diagnosis, about 70% of patients have extensive-stage disease, defined as the presence of metastatic disease by imaging or physical examination outside the hemithorax; the remaining 30% of patients have limited-stage disease, in which tumor involvement is confined to one hemithorax and can be treated in a tolerable radiation field.

Author Info: (1) Department of Medical Oncology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. (2) Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New

Author Info: (1) Department of Medical Oncology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. (2) Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

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Reproducibility of PD-L1 assessment in non-small cell lung cancer-know your limits but never stop trying to exceed them

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Immunotherapy targeting the programmed death 1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway has demonstrated strong and durable anti-tumoral immune responses with significantly improved overall survival in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) (1). PD-1 or CD279 is a type 1 transmembrane protein expressed on the surface of activated immune cells, including T cells, B cells, monocytes, natural killer cells, regulatory T cells, dendritic cells, and macrophages (2). The binding of PD-1 to its major ligand PD-L1, B7-H1 or CD274 decreases the ability of activated T cells to produce an effective immune response and prevents the host immune system from destroying tumor cells. PD-L1 is widely expressed in hematopoietic cells, including macrophages, dendritic cells, mast cells, T cells, and B cells, as well as in non-hematopoietic cells, including epithelial, endothelial, and tumor cells (2).

Author Info: (1) Universite Cote d'Azur, University Hospital Federation OncoAge, Laboratory of Clinical and Experimental Pathology, Pasteur Hospital, Nice, France. Universite Cote d'Azur, Institute for Research on

Author Info: (1) Universite Cote d'Azur, University Hospital Federation OncoAge, Laboratory of Clinical and Experimental Pathology, Pasteur Hospital, Nice, France. Universite Cote d'Azur, Institute for Research on Cancer and Ageing, Nice (IRCAN), Inserm U1081 and UMR CNRS 7284, Nice, France. Universite Cote d'Azur, University Hospital Federation OncoAge, Hospital-Related Biobank (BB-0033-00025), Pasteur Hospital, Nice, France. (2) Universite Cote d'Azur, University Hospital Federation OncoAge, Laboratory of Clinical and Experimental Pathology, Pasteur Hospital, Nice, France. Universite Cote d'Azur, Institute for Research on Cancer and Ageing, Nice (IRCAN), Inserm U1081 and UMR CNRS 7284, Nice, France. Universite Cote d'Azur, University Hospital Federation OncoAge, Hospital-Related Biobank (BB-0033-00025), Pasteur Hospital, Nice, France.

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Regulation of PD-1/PD-L1 pathway and resistance to PD-1/PD-L1 blockade

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Immune checkpoint blockades, such as inhibitors against programmed death 1 (PD-1) and its ligand (PD-L1), have received extensive attention in the past decade because of their dramatic clinical outcomes in advanced malignancies. However, both primary and acquired resistance becomes one of the major obstacles, which greatly limits the long-lasting effects and wide application of PD-1/PD-L1 blockade therapy. PD-1/PD-L1 both regulates and is regulated by cellular signaling pathways and epigenetic modification, thus inhibiting the proliferation and effector function of T and B cells. The lack of tumor antigens and effective antigen presentation, aberrant activation of oncogenic pathways, mutations in IFN-gamma signaling, immunosuppressive tumor microenvironment such as regulatory T cells, myeloid-derived suppressor cells, M2 macrophages, and immunoinhibitory cytokines can lead to resistance to PD-1/PD-L1 blockade. In this review, we describe PD-1 related signaling pathways, essential factors contributing to the resistance of PD-1 blockade, and discuss strategies to increase the efficacy of immunotherapy. Furthermore, we discuss the possibility of combined epigenetic therapy with PD-1 blockade as a potential promising approach for cancer treatment.

Author Info: (1) Department of Molecular Biology and Bio-Therapeutic, School of Life Science, Chinese PLA General Hospital, Beijing 100853, China. (2) Department of Molecular Biology and Bio-Therapeutic

Author Info: (1) Department of Molecular Biology and Bio-Therapeutic, School of Life Science, Chinese PLA General Hospital, Beijing 100853, China. (2) Department of Molecular Biology and Bio-Therapeutic, School of Life Science, Chinese PLA General Hospital, Beijing 100853, China. (3) Department of Molecular Biology and Bio-Therapeutic, School of Life Science, Chinese PLA General Hospital, Beijing 100853, China. (4) Department of Molecular Biology and Bio-Therapeutic, School of Life Science, Chinese PLA General Hospital, Beijing 100853, China. (5) Department of Molecular Biology and Bio-Therapeutic, School of Life Science, Chinese PLA General Hospital, Beijing 100853, China. (6) Department of Molecular Biology and Bio-Therapeutic, School of Life Science, Chinese PLA General Hospital, Beijing 100853, China.

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