T antigen–specific CD8+ T cells associate with PD-1 blockade response in virus-positive Merkel cell carcinoma
Ulla Kring Hansen, Candice D. Church, Ana Micaela Carnaz Simões, Marcus Svensson Frej, Amalie Kai Bentzen, Siri A. Tvingsholm, Jürgen C. Becker, Steven P. Fling, Nirasha Ramchurren, Suzanne L. Topalian, Paul T. Nghiem, Sine Reker Hadrup
Ulla Kring Hansen, Candice D. Church, Ana Micaela Carnaz Simões, Marcus Svensson Frej, Amalie Kai Bentzen, Siri A. Tvingsholm, Jürgen C. Becker, Steven P. Fling, Nirasha Ramchurren, Suzanne L. Topalian, Paul T. Nghiem, Sine Reker Hadrup
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Research Article Immunology Oncology

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

Abstract

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.

Authors

Ulla Kring Hansen, Candice D. Church, Ana Micaela Carnaz Simões, Marcus Svensson Frej, Amalie Kai Bentzen, Siri A. Tvingsholm, Jürgen C. Becker, Steven P. Fling, Nirasha Ramchurren, Suzanne L. Topalian, Paul T. Nghiem, Sine Reker Hadrup

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Figure 6

Functional capacity of T-Ag–expanded cells.

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Functional capacity of T-Ag–expanded cells. (A) The frequencies of multi...
(A) The frequencies of multifunctional CD8+ T cells being double- or triple-positive for IFN-γ, TNF-α, and CD107a after a 10-hour coculture between HLA-matched TCLs and either unexpanded (n = 7) or expanded cells (n = 12). The cocultures were run at 2 E:T ratios; 1:1 (top) and 2:1 (bottom). *P < 0.05, Wilcoxon’s rank-sum test. Box plots displaying the interquartile range. (B) The percentage of TCL change after 72-hour coculture between HLA-matched, MCC TCL, and unexpanded/expanded or irrelevant healthy donor (HD) cells run in the Incucyte instrument. (C) Comparison in tumor cell change between paired unexpanded and expanded cells (n = 4). **P < 0.01, Wilcoxon’s rank-sum test. Box plots displaying interquartile range. (D) Kinetics of tumor cell growth during T cell coculture for 72 hours. Patient samples have been divided based on detectable/undetectable T-Ag–specific precursor T cells prior to expansion. (E) Killing half-time, 50% reduction in tumor cells, for coculture with T-Ag–expanded T cell samples.