Prevalent and Diverse Intratumoral Oncoprotein-Specific CD8+ T Cells within Polyomavirus-Driven Merkel Cell Carcinomas
| العنوان: | Prevalent and Diverse Intratumoral Oncoprotein-Specific CD8+ T Cells within Polyomavirus-Driven Merkel Cell Carcinomas |
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| المؤلفون: | Aude G. Chapuis, Rima M. Kulikauskas, Aric Colunga, Hong Xie, Kelly G. Paulson, Paul Nghiem, Maclean M. Cook, Alexander L. Greninger, Olga K. Afanasiev, Jayasri G. Iyer, David M. Koelle, Lichen Jing, Mariliis Ott, Candice D. Church, Dafina Ibrani, Shailender Bhatia |
| المصدر: | Cancer Immunol Res |
| بيانات النشر: | American Association for Cancer Research (AACR), 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Adult, Male, 0301 basic medicine, Cancer Research, Skin Neoplasms, Carcinogenesis, Immunology, Merkel cell polyomavirus, chemical and pharmacologic phenomena, Human leukocyte antigen, CD8-Positive T-Lymphocytes, Article, Epitope, Epitopes, Young Adult, 03 medical and health sciences, Lymphocytes, Tumor-Infiltrating, 0302 clinical medicine, Immune system, Antigen, medicine, Humans, Cytotoxic T cell, Antigens, Viral, Tumor, Aged, biology, Merkel cell carcinoma, Middle Aged, biology.organism_classification, medicine.disease, Carcinoma, Merkel Cell, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Cancer research, Female, Immunotherapy, Merkel cell |
| الوصف: | Merkel cell carcinoma (MCC) is often caused by persistent expression of Merkel cell polyomavirus (MCPyV) T-antigen (T-Ag). These non-self proteins comprise about 400 amino acids (AA). Clinical responses to immune checkpoint inhibitors, seen in about half of patients, may relate to T-Ag–specific T cells. Strategies to increase CD8+ T-cell number, breadth, or function could augment checkpoint inhibition, but vaccines to augment immunity must avoid delivery of oncogenic T-antigen domains. We probed MCC tumor-infiltrating lymphocytes (TIL) with an artificial antigen-presenting cell (aAPC) system and confirmed T-Ag recognition with synthetic peptides, HLA-peptide tetramers, and dendritic cells (DC). TILs from 9 of 12 (75%) subjects contained CD8+ T cells recognizing 1–8 MCPyV epitopes per person. Analysis of 16 MCPyV CD8+ TIL epitopes and prior TIL data indicated that 97% of patients with MCPyV+ MCC had HLA alleles with the genetic potential that restrict CD8+ T-cell responses to MCPyV T-Ag. The LT AA 70–110 region was epitope rich, whereas the oncogenic domains of T-Ag were not commonly recognized. Specific recognition of T-Ag–expressing DCs was documented. Recovery of MCPyV oncoprotein–specific CD8+ TILs from most tumors indicated that antigen indifference was unlikely to be a major cause of checkpoint inhibition failure. The myriad of epitopes restricted by diverse HLA alleles indicates that vaccination can be a rational component of immunotherapy if tumor immune suppression can be overcome, and the oncogenic regions of T-Ag can be modified without impacting immunogenicity. |
| تدمد: | 2326-6074 2326-6066 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b6357e34f8f52391095463a2338f76c6 https://doi.org/10.1158/2326-6066.cir-19-0647 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....b6357e34f8f52391095463a2338f76c6 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 23266074 23266066 |
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