T antigen–specific CD8+ T cells associate with PD-1 blockade response in virus-positive Merkel cell carcinoma
Ulla Kring Hansen, … , Paul T. Nghiem, Sine Reker Hadrup
Ulla Kring Hansen, … , Paul T. Nghiem, Sine Reker Hadrup
Published January 30, 2024
Citation Information: J Clin Invest. 2024;134(8):e177082. https://doi.org/10.1172/JCI177082.
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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 3

T-Ag–reactive T cells are associated with clinical benefit of ICI.

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T-Ag–reactive T cells are associated with clinical benefit of ICI. (A) N...
(A) Number of T-Ag–reactive T cell populations detected during ICI therapy. The patients are divided based on their RECIST criteria into responders (CR and PR, n = 17) and nonresponders (SD and PD, n = 7) and colored accordingly with size of circles indicating the summed estimated (est.) frequency of T-Ag–reactive T cells out of CD8+. *P < 0.05, 2-way ANOVA. (B) Number of T-Ag–specific T cells detected for the 2 patient groups before and after therapy initiation. The pooled posttherapy number was based on either 3-week or 12-week time points or an average of both. *P < 0.05, Kruskal-Wallis test with Dunn’s correction. (C) The sum of estimated frequency of T-Ag–reactive T cells before and after therapy for patient groups. *P < 0.05, Kruskal-Wallis test with Dunn’s correction. (D) Change in the sum of estimated frequency before and after therapy. *P < 0.05, Mann-Whitney U test. (E) Number of VP1- and CEF-specific T cells detected for the 2 patient groups before and after therapy initiation. B–E are presented with box plots displaying the interquartile range. (F) Progression-free survival curves split based on detectable (n = 13) or nondetectable (n = 7) T-Ag–reactive T cells at any time point after ICI therapy initiation. Significance levels and hazard ratios are denoted; log-rank (Mantel-Cox) test. (G) Progression-free survival curves for detectable (Detect.) T-Ag–reactive T cells split by median baseline tumor burden (diameter = 42 mm) and for nondetectable (Nondetect.) T-Ag–reactive T cells split by median baseline tumor burden (diameter = 15 mm). Significance levels are denoted, log-rank (Mantel-Cox) test. TB, tumor burden.