ABSTRACT
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
ABSTRACT
Understanding resistance to antibody to programmed cell death protein 1 (PD-1; anti-PD-1) is crucial for the development of reversal strategies. In anti-PD-1-resistant models, simultaneous anti-PD-1 and vaccine therapy reversed resistance, while PD-1 blockade before antigen priming abolished therapeutic outcomes. This was due to induction of dysfunctional PD-1+CD38hi CD8+ cells by PD-1 blockade in suboptimally primed CD8 cell conditions induced by tumors. This results in erroneous T cell receptor signaling and unresponsiveness to antigenic restimulation. On the other hand, PD-1 blockade of optimally primed CD8 cells prevented the induction of dysfunctional CD8 cells, reversing resistance. Depleting PD-1+CD38hi CD8+ cells enhanced therapeutic outcomes. Furthermore, non-responding patients showed more PD-1+CD38+CD8+ cells in tumor and blood than responders. In conclusion, the status of CD8+ T cell priming is a major contributor to anti-PD-1 therapeutic resistance. PD-1 blockade in unprimed or suboptimally primed CD8 cells induces resistance through the induction of PD-1+CD38hi CD8+ cells that is reversed by optimal priming. PD-1+CD38hi CD8+ cells serve as a predictive and therapeutic biomarker for anti-PD-1 treatment. Sequencing of anti-PD-1 and vaccine is crucial for successful therapy.
Subject(s)
ADP-ribosyl Cyclase 1/metabolism , CD8-Positive T-Lymphocytes/immunology , Drug Resistance, Neoplasm/immunology , Membrane Glycoproteins/metabolism , Neoplasms/immunology , Programmed Cell Death 1 Receptor/immunology , ADP-ribosyl Cyclase 1/genetics , Animals , Antibodies/immunology , CD8-Positive T-Lymphocytes/pathology , Cancer Vaccines/immunology , Cell Line, Tumor , Drug Resistance, Neoplasm/genetics , Female , Humans , Immunotherapy/methods , Membrane Glycoproteins/genetics , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Tumor Microenvironment/immunologyABSTRACT
Treatment of cancer has been revolutionized by immune checkpoint blockade therapies. Despite the high rate of response in advanced melanoma, the majority of patients succumb to disease. To identify factors associated with success or failure of checkpoint therapy, we profiled transcriptomes of 16,291 individual immune cells from 48 tumor samples of melanoma patients treated with checkpoint inhibitors. Two distinct states of CD8+ T cells were defined by clustering and associated with patient tumor regression or progression. A single transcription factor, TCF7, was visualized within CD8+ T cells in fixed tumor samples and predicted positive clinical outcome in an independent cohort of checkpoint-treated patients. We delineated the epigenetic landscape and clonality of these T cell states and demonstrated enhanced antitumor immunity by targeting novel combinations of factors in exhausted cells. Our study of immune cell transcriptomes from tumors demonstrates a strategy for identifying predictors, mechanisms, and targets for enhancing checkpoint immunotherapy.
Subject(s)
CD8-Positive T-Lymphocytes/immunology , Immunotherapy/methods , Melanoma/immunology , Transcriptome , Animals , Antibodies, Monoclonal, Humanized/immunology , Antibodies, Monoclonal, Humanized/pharmacology , Antigens, CD/immunology , Antineoplastic Agents, Immunological/immunology , Antineoplastic Agents, Immunological/pharmacology , Apyrase/antagonists & inhibitors , Apyrase/immunology , Cell Line, Tumor , Humans , Leukocyte Common Antigens/antagonists & inhibitors , Leukocyte Common Antigens/immunology , Melanoma/therapy , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , T Cell Transcription Factor 1/metabolismABSTRACT
Treatment with immune checkpoint blockade (CPB) therapies often leads to prolonged responses in patients with metastatic melanoma, but the common mechanisms of primary and acquired resistance to these agents remain incompletely characterized and have yet to be validated in large cohorts. By analyzing longitudinal tumor biopsies from 17 metastatic melanoma patients treated with CPB therapies, we observed point mutations, deletions or loss of heterozygosity (LOH) in beta-2-microglobulin (B2M), an essential component of MHC class I antigen presentation, in 29.4% of patients with progressing disease. In two independent cohorts of melanoma patients treated with anti-CTLA4 and anti-PD1, respectively, we find that B2M LOH is enriched threefold in non-responders (~30%) compared to responders (~10%) and associated with poorer overall survival. Loss of both copies of B2M is found only in non-responders. B2M loss is likely a common mechanism of resistance to therapies targeting CTLA4 or PD1.
