HLA class I loss in metachronous metastases prevents continuous T cell recognition of mutated neoantigens in a human melanoma model
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Barbara Schrörs1, Silke Lübcke1, Volker Lennerz1, Martina Fatho1, Anne Bicker2, Catherine Wölfel1, Patrick Derigs1, Thomas Hankeln2, Dirk Schadendorf3, Annette Paschen3, Thomas Wölfel1
1Internal Medicine III, University Cancer Center (UCT) and Research Center for Immunotherapy (FZI), University Medical Center (UMC) of the Johannes Gutenberg University and German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, Mainz, Germany
2Institute for Molecular Genetics, Johannes Gutenberg University, Mainz, Germany
3Department of Dermatology, University Hospital, University Duisburg-Essen and German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf, Essen, Germany
Thomas Wölfel, email: email@example.com
Keywords: melanoma, mutated neoantigens, high-throughput sequencing, immune escape, HLA class I loss
Received: July 05, 2016 Accepted: February 27, 2017 Published: March 09, 2017
T lymphocytes against tumor-specific mutated neoantigens can induce tumor regression. Also, the size of the immunogenic cancer mutanome is supposed to correlate with the clinical efficacy of checkpoint inhibition. Herein, we studied the susceptibility of tumor cell lines from lymph node metastases occurring in a melanoma patient over several years towards blood-derived, neoantigen-specific CD8+ T cells. In contrast to a cell line established during early stage III disease, all cell lines generated at later time points from stage IV metastases exhibited partial or complete loss of HLA class I expression. Whole exome and transcriptome sequencing of the four tumor lines and a germline control were applied to identify expressed somatic single nucleotide substitutions (SNS), insertions and deletions (indels). Candidate peptides encoded by these variants and predicted to bind to the patient’s HLA class I alleles were synthesized and tested for recognition by autologous mixed lymphocyte-tumor cell cultures (MLTCs). Peptides from four mutated proteins, HERPUD1G161S, INSIG1S238F, MMS22LS437F and PRDM10S1050F, were recognized by MLTC responders and MLTC-derived T cell clones restricted by HLA-A*24:02 or HLA-B*15:01. Intracellular peptide processing was verified with transfectants. All four neoantigens could only be targeted on the cell line generated during early stage III disease. HLA loss variants of any kind were uniformly resistant. These findings corroborate that, although neoantigens represent attractive therapeutic targets, they also contribute to the process of cancer immunoediting as a serious limitation to specific T cell immunotherapy.
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