Transcriptional and functional analyses of neoantigen-specific CD4 T cells during a profound response to anti-PD-L1 in metastatic Merkel cell carcinoma.

Autor:	Church C; Division of Dermatology, Department of Medicine, University of Washington, Seattle, WA, USA., Pulliam T; Division of Dermatology, Department of Medicine, University of Washington, Seattle, WA, USA., Longino N; Division of Dermatology, Department of Medicine, University of Washington, Seattle, WA, USA., Park SY; Division of Dermatology, Department of Medicine, University of Washington, Seattle, WA, USA., Smythe KS; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA., Makarov V; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.; Center for Immunotherapy and Precision Immuno-oncology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA., Riaz N; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA., Jing L; Department of Medicine, University of Washington, Seattle, Washington, USA., Amezquita R; Biostatistics Bioinformatics and Epidemiology Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA., Campbell JS; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA., Gottardo R; Biostatistics Bioinformatics and Epidemiology Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA.; Lausanne University Hospital, Lausanne, Vaud, Switzerland.; Swiss Institute of Bioinformatics, Lausanne, Switzerland., Pierce RH; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA., Choi J; Department of Dermatology, Biochemistry & Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA., Chan TA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.; Center for Immunotherapy and Precision Immuno-oncology, Cleveland Clinic, Cleveland, Ohio, USA., Koelle DM; Department of Medicine, University of Washington, Seattle, Washington, USA.; Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA.; Department of Global Health, University of Washington, Seattle, WA, USA.; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA.; Benaroya Research Institute, Seattle, WA, USA., Nghiem P; Division of Dermatology, Department of Medicine, University of Washington, Seattle, WA, USA pnghiem@uw.edu.; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
Jazyk:	angličtina
Zdroj:	Journal for immunotherapy of cancer [J Immunother Cancer] 2022 Sep; Vol. 10 (9).
DOI:	10.1136/jitc-2022-005328
Abstrakt:	Background: Merkel cell carcinoma (MCC) often responds to PD-1 pathway blockade, regardless of tumor-viral status (~80% of cases driven by the Merkel cell polyomavirus (MCPyV)). Prior studies have characterized tumor-specific T cell responses to MCPyV, which have typically been CD8, but little is known about the T cell response to UV-induced neoantigens. Methods: A patient in her mid-50s with virus-negative (VN) MCC developed large liver metastases after a brief initial response to chemotherapy. She received anti-PD-L1 (avelumab) and had a partial response within 4 weeks. Whole exome sequencing (WES) was performed to determine potential neoantigen peptides. Characterization of peripheral blood neoantigen T cell responses was evaluated via interferon-gamma (IFNγ) ELISpot, flow cytometry and single-cell RNA sequencing. Tumor-resident T cells were characterized by multiplexed immunohistochemistry. Results: WES identified 1027 tumor-specific somatic mutations, similar to the published average of 1121 for VN-MCCs. Peptide prediction with a binding cut-off of ≤100 nM resulted in 77 peptides that were synthesized for T cell assays. Although peptides were predicted based on class I HLAs, we identified circulating CD4 T cells targeting 5 of 77 neoantigens. In contrast, no neoantigen-specific CD8 T cell responses were detected. Neoantigen-specific CD4 T cells were undetectable in blood before anti-PD-L1 therapy but became readily detectible shortly after starting therapy. T cells produced robust IFNγ when stimulated by neoantigen (mutant) peptides but not by the normal (wild-type) peptides. Single cell RNAseq showed neoantigen-reactive T cells expressed the Th1-associated transcription factor (T-bet) and associated cytokines. These CD4 T cells did not significantly exhibit cytotoxicity or non-Th1 markers. Within the pretreatment tumor, resident CD4 T cells were also Th1-skewed and expressed T-bet. Conclusions: We identified and characterized tumor-specific Th1-skewed CD4 T cells targeting multiple neoantigens in a patient who experienced a profound and durable partial response to anti-PD-L1 therapy. To our knowledge, this is the first report of neoantigen-specific T cell responses in MCC. Although CD4 and CD8 T cells recognizing viral tumor antigens are often detectible in virus-positive MCC, only CD4 T cells recognizing neoantigens were detected in this patient. These findings suggest that CD4 T cells can play an important role in the response to anti-PD-(L)1 therapy. Competing Interests: Competing interests: PN reports personal fees from Pfizer, Inc, Bristol Myers Squibb, EMD Serono, Rain Therapeutics, Almirall, and Instill Bio. In addition, PN has pending patents for ‘Merkel cell polyomavirus T antigen-specific TCRs and uses thereof’ and ‘Novel epitopes as T cell targets in Merkel Cell Carcinoma (MCC)’. CC has a pending patent ‘Merkel cell polyomavirus T antigen-specific TCRs and uses thereof’. VM reports a patent (#EP3090066A2), Determinants of cancer response to immunotherapy. NR reports grants from REPARE Therapuetics, Repertoire Immune Medicines, and from Bristol Myers Squibb. RA is an employee of and reports stocks in Pfizer. JSC reports stock from Sensei Bio. RG reports personal fees from Takeda, Ozette Technologies, and Modulus Therapeutics. RHP is an employee of and reports stock in Sensei Bio. TC reports stock from Gritstone Bio, grants from Pfizer and InterVenn, personal fees from Illumina, and royalties from PGDx. Additionally, TC has a patent ‘Use of TMB to identify immunotherapy responders licensed to PGDx’. DK reports grants from Sensei Bio and a pending patent related to ‘high-affinity T-cell receptors that target the Merkel polyomavirus’. (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu