Abstract
Understanding mechanisms of late/acquired cancer immunotherapy resistance is critical to improve outcomes; cellular immunotherapy trials offer a means to probe complex tumor-immune interfaces through defined T cell/antigen interactions. We treated two patients with metastatic Merkel cell carcinoma with autologous Merkel cell polyomavirus specific CD8+ T cells and immune-checkpoint inhibitors. In both cases, dramatic remissions were associated with dense infiltration of activated CD8+s into the regressing tumors. However, late relapses developed at 22 and 18 months, respectively. Here we report single cell RNA sequencing identified dynamic transcriptional suppression of the specific HLA genes presenting the targeted viral epitope in the resistant tumor as a consequence of intense CD8-mediated immunologic pressure; this is distinguished from genetic HLA-loss by its reversibility with drugs. Transcriptional suppression of Class I loci may underlie resistance to other immunotherapies, including checkpoint inhibitors, and have implications for the design of improved immunotherapy treatments.
MeSH terms
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Antineoplastic Agents, Immunological / therapeutic use
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CD8-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / transplantation
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Carcinoma, Merkel Cell / genetics
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Carcinoma, Merkel Cell / immunology
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Carcinoma, Merkel Cell / therapy*
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Carcinoma, Merkel Cell / virology
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Costimulatory and Inhibitory T-Cell Receptors / antagonists & inhibitors
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Gene Expression Regulation, Neoplastic
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Genes, MHC Class I / genetics*
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Genes, MHC Class I / immunology
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Humans
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Immunotherapy, Adoptive / methods*
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Lymphocytes, Tumor-Infiltrating / immunology
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Lymphocytes, Tumor-Infiltrating / transplantation
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Male
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Merkel cell polyomavirus / immunology
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Merkel cell polyomavirus / isolation & purification
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Middle Aged
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Neoplasm Recurrence, Local / genetics*
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Neoplasm Recurrence, Local / immunology
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Polyomavirus Infections / genetics
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Polyomavirus Infections / immunology
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Polyomavirus Infections / therapy*
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Polyomavirus Infections / virology
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Sequence Analysis, RNA / methods
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Single-Cell Analysis / methods
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Skin Neoplasms / genetics
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Skin Neoplasms / immunology
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Skin Neoplasms / therapy*
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Skin Neoplasms / virology
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Testicular Neoplasms / immunology
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Testicular Neoplasms / secondary
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Testicular Neoplasms / virology
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Transcription, Genetic / immunology
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Transplantation, Autologous / methods
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Tumor Escape / genetics*
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Tumor Virus Infections / genetics
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Tumor Virus Infections / immunology
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Tumor Virus Infections / therapy*
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Tumor Virus Infections / virology
Substances
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Antineoplastic Agents, Immunological
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Costimulatory and Inhibitory T-Cell Receptors