Merkel cell carcinoma UV-neoantigen-specific T cells in the context of PD1 checkpoint blockade
Candice Church1, Vladimir Markarov2, Nadeem Riaz2, Timothy Chan2, Jaehyuk Choi3, Paul Nghiem1
1Univ of Washington School of Medicine, Division of Dermatology, Seattle WA; 2Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY; 3Depts of Dermatology, Biochemistry & Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL
Merkel cell carcinoma (MCC) is a rare but often deadly skin cancer with a disease-associated mortality three times that of melanoma. In 80% of cases, a truncated Merkel cell polyomavirus (MCPyV) is clonally integrated and drives oncogenesis while the remaining 20% of MCCs do not contain MCPyV and arise from UV-mutagenesis. MCPyV-negative tumors have higher mutational burdens than any other epithelial based cancer types analyzed in The Cancer Genome Atlas, suggesting these tumors harbor high numbers of neoantigens. We characterized the UV-neoantigen T cell response in a patient whose MCC tumor was negative for MCPyV, but who had a rapid and durable response to anti-PD-L1 therapy. Whole exome sequencing revealed 1,027 non-synonymous mutations in the tumor exome. 263 neoantigens were predicted to bind patient’s HLA class I molecules with a binding affinity (IC50) of 500nM or less. Of these 263 predicted UV-neoantigens, 77 were considered high affinity (IC50 <100nM) and were selected for peptide synthesis. 5 of 77 UV-neoantigen peptides elicited an interferon gamma (IFNg) response as measured by Enzyme Linked Immunospot. Of those, 4 were strictly UV-neoantigen-specific as they did not produce IFNg upon exposure to the corresponding wildtype peptides. Surprisingly, these IFNg producing lymphocytes were determined to be CD4 T cells even though peptide selection was based on HLA class I. To our knowledge, this is the first report of UV-neoantigen specific T cells in MCC. These preliminary data demonstrate that an anti-UV-neoantigen T cell response, in part mediated by CD4 T cells, could be a key factor in successful anti-PD-L1 responses in MCC as well as other UV-associated skin cancers.
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