T antigen-specific CD8+ T cells associate with PD-1 blockade response in virus-positive Merkel cell carcinoma.

Autor:	Hansen UK; Section of Experimental and Translational Immunology, Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark.; PokeAcell Aps, BioInnovation Institute, Copenhagen, Denmark., Church CD; Department of Dermatology, Department of Medicine, University of Washington, Seattle, Washington, USA., Carnaz Simões AM; PokeAcell Aps, BioInnovation Institute, Copenhagen, Denmark., Frej MS; Section of Experimental and Translational Immunology, Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark.; PokeAcell Aps, BioInnovation Institute, Copenhagen, Denmark., Bentzen AK; Section of Experimental and Translational Immunology, Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark., Tvingsholm SA; Section of Experimental and Translational Immunology, Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark., Becker JC; Department of Translational Skin Cancer Research, University Hospital Essen and German Cancer Consortium (DKTK), Essen, Germany.; German Cancer Research Center (DKFZ), Heidelberg, Germany.; Department of Dermatology, University Hospital Essen, Essen, Germany., Fling SP; Fred Hutchinson Cancer Center, Seattle, Washington, USA., Ramchurren N; Fred Hutchinson Cancer Center, Seattle, Washington, USA., Topalian SL; Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.; Bloomberg-Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA., Nghiem PT; Department of Dermatology, Department of Medicine, University of Washington, Seattle, Washington, USA.; Fred Hutchinson Cancer Center, Seattle, Washington, USA., Hadrup SR; Section of Experimental and Translational Immunology, Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark.
Jazyk:	angličtina
Zdroj:	The Journal of clinical investigation [J Clin Invest] 2024 Jan 30; Vol. 134 (8). Date of Electronic Publication: 2024 Jan 30.
DOI:	10.1172/JCI177082
Abstrakt:	Merkel cell carcinoma (MCC) is a highly immunogenic skin cancer primarily induced by Merkel cell polyomavirus, which is driven by the expression of the oncogenic T antigens (T-Ags). Blockade of the programmed cell death protein-1 (PD-1) pathway has shown remarkable response rates, but evidence for therapy-associated T-Ag-specific immune response and therapeutic strategies for the nonresponding fraction are both limited. We tracked T-Ag-reactive CD8+ T cells in peripheral blood of 26 MCC patients under anti-PD1 therapy, using DNA-barcoded pMHC multimers, displaying all peptides from the predicted HLA ligandome of the oncoproteins, covering 33 class I haplotypes. We observed a broad T cell recognition of T-Ags, including identification of 20 T-Ag-derived epitopes we believe to be novel. Broadening of the T-Ag recognition profile and increased T cell frequencies during therapy were strongly associated with clinical response and prolonged progression-free survival. T-Ag-specific T cells could be further boosted and expanded directly from peripheral blood using artificial antigen-presenting scaffolds, even in patients with no detectable T-Ag-specific T cells. These T cells provided strong tumor-rejection capacity while retaining a favorable phenotype for adoptive cell transfer. These findings demonstrate that T-Ag-specific T cells are associated with the clinical outcome to PD-1 blockade and that Ag-presenting scaffolds can be used to boost such responses.
Databáze:	MEDLINE
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