Prevalent and Diverse Intratumoral Oncoprotein-Specific CD8+ T Cells within Polyomavirus-Driven Merkel Cell Carcinomas

Cancer Immunol Res. 2020 May;8(5):648-659. doi: 10.1158/2326-6066.CIR-19-0647. Epub 2020 Mar 16.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antigens, Viral, Tumor / immunology*
  • Antigens, Viral, Tumor / metabolism
  • CD8-Positive T-Lymphocytes / immunology*
  • Carcinogenesis / immunology
  • Carcinoma, Merkel Cell / immunology*
  • Carcinoma, Merkel Cell / therapy
  • Epitopes / immunology*
  • Female
  • Humans
  • Immunotherapy / methods
  • Lymphocytes, Tumor-Infiltrating / immunology*
  • Male
  • Merkel cell polyomavirus / immunology*
  • Middle Aged
  • Skin Neoplasms / immunology*
  • Skin Neoplasms / therapy
  • Young Adult


  • Antigens, Viral, Tumor
  • Epitopes