Research

T cell recognition of large T and small T antigen in Merkel cell polyomavirus-associated cancer

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Abstract

Merkel Cell Carcinoma is an aggressive human skin cancer induced by Merkel Cell Polyomavirus (MCPyV). MCPyV is commonly found in human, but the oncogenic transformation takes place during immunosuppression. Two mutation events allow the clonal integration of the viral genome into the host genome and translation of the two viral genes large T (LTA) and small T antigen (STA). Standard treatment with chemotherapy shows poor clinical outcome instead immunotherapy offers new potential treatment strategies. The use of PD-1 checkpoint inhibi-tors has shown promising results (>50% response rates, RECIST). However, not all patients are able to mount an immune response. Instead adoptive transfer of MCPyV-reactive T cells is an attractive strategy for this cohort. We have previously identiﬁed T cell epitopes from the MCPyV-derived proteins LTA, STA and VP1. Here we aim to expand the knowledge about T cell epitopes by including a broader range of HLA restrictions. We analyzed 31 patients’ peripheral blood mononuclear cells through enrichment of low frequency clones, followed by revealing of T cell reactivity using combinatorial color-encoded peptide-MHC multimers. 28 T cell responses against 18 MCPyV-derived peptides were detected. Addi-tional testing has conﬁrmed functional T cell reactivity against one of these epitopes. We analyzed 3 patients’ tumor inﬁltrating lymphocytes by direct ex-vivo detection of T cell reactivity using combinatorial color-encoded peptide-MHC multimers. 5 T cell responses against 5 peptides were detected. The functional T cell response towards detected epitopes is under investigation in order to characterize them as potential T cell targets in a new therapy.