Open AccessPrevalent and Diverse Intratumoral Oncoprotein-Specific CD8+ T Cells within Polyomavirus-Driven Merkel Cell Carcinomas
Author(s) -
Lichen Jing,
Mariliis Ott,
Candice D. Church,
Rima M. Kulikauskas,
Dafina Ibrani,
Jayasri G. Iyer,
Olga K. Afanasiev,
Paul Nghiem,
Matthew A. Cook,
Hong Xie,
Alexander L. Greninger,
Kelly G. Paulson,
Aude G. Chapuis,
Shailender Bhatia,
Paul Nghiem,
David M. Koelle
Publication year - 2020
Publication title -
cancer immunology research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.976
H-Index - 87
eISSN - 2326-6074
pISSN - 2326-6066
DOI - 10.1158/2326-6066.cir-19-0647
Subject(s) - merkel cell polyomavirus , epitope , merkel cell carcinoma , biology , cd8 , antigen , cytotoxic t cell , immunogenicity , immunotherapy , cancer immunotherapy , t cell , immune system , merkel cell , cancer research , immunology , immune checkpoint , human leukocyte antigen , virology , carcinoma , genetics , in vitro
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.