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

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 t...

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Bibliographic Details
Published in:The Journal of clinical investigation 2024-04, Vol.134 (8), p.1-14
Main Authors: Hansen, Ulla Kring, Church, Candice D, Carnaz Simões, Ana Micaela, Frej, Marcus Svensson, Bentzen, Amalie Kai, Tvingsholm, Siri A, Becker, Jürgen C, Fling, Steven P, Ramchurren, Nirasha, Topalian, Suzanne L, Nghiem, Paul T, Hadrup, Sine Reker
Format: Article
Language:English
Subjects:
Antigens
Antigens, Viral, Tumor
Apoptosis
Carcinoma
Carcinoma, Merkel Cell - drug therapy
Carcinoma, Merkel Cell - genetics
CD8 antigen
CD8-Positive T-Lymphocytes
Cell death
Cell recognition
Epitopes
Genotype & phenotype
Haplotypes
Humans
Immunogenicity
Immunotherapy
Influenza
Ligands
Lymphocytes
Lymphocytes T
Patients
PD-1 protein
Peptides
Peripheral blood
Phenotypes
Programmed Cell Death 1 Receptor - genetics
Proteins
Response rates
Skin cancer
Skin Neoplasms - drug therapy
Skin Neoplasms - genetics
Tumors
Viruses
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Summary: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.
ISSN:1558-8238
0021-9738
1558-8238
DOI:10.1172/JCI177082