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23266066cir200817-sup-252550_2_supp_6923749_qqm7ql.pdf (7.05 MB)

Supplementary Figures from γδ T Cells in Merkel Cell Carcinomas Have a Proinflammatory Profile Prognostic of Patient Survival

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posted on 2023-04-04, 01:04 authored by Nicholas A. Gherardin, Kelly Waldeck, Alex Caneborg, Luciano G. Martelotto, Shiva Balachander, Magnus Zethoven, Pasquale M. Petrone, Andrew Pattison, James S. Wilmott, Sergio M. Quiñones-Parra, Fernando Rossello, Atara Posner, Annie Wong, Alison M. Weppler, Kerwin F. Shannon, Angela Hong, Peter M. Ferguson, Valerie Jakrot, Jeanette Raleigh, Athena Hatzimihalis, Paul J. Neeson, Paolo Deleso, Meredith Johnston, Margaret Chua, Juergen C. Becker, Shahneen Sandhu, Grant A. McArthur, Anthony J. Gill, Richard A. Scolyer, Rodney J. Hicks, Dale I. Godfrey, Richard W. Tothill

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National Health and Medical Research Council of Australia

Australian Research Council

NHMRC

Medical Research Future Fund

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ARTICLE ABSTRACT

Merkel cell carcinomas (MCC) are immunogenic skin cancers associated with viral infection or UV mutagenesis. To study T-cell infiltrates in MCC, we analyzed 58 MCC lesions from 39 patients using multiplex-IHC/immunofluorescence (m-IHC/IF). CD4+ or CD8+ T cells comprised the majority of infiltrating T lymphocytes in most tumors. However, almost half of the tumors harbored prominent CD4/CD8 double-negative (DN) T-cell infiltrates (>20% DN T cells), and in 12% of cases, DN T cells represented the majority of T cells. Flow cytometric analysis of single-cell suspensions from fresh tumors identified DN T cells as predominantly Vδ2− γδ T cells. In the context of γδ T–cell inflammation, these cells expressed PD-1 and LAG3, which is consistent with a suppressed or exhausted phenotype, and CD103, which indicates tissue residency. Furthermore, single-cell RNA sequencing (scRNA-seq) identified a transcriptional profile of γδ T cells suggestive of proinflammatory potential. T-cell receptor (TCR) analysis confirmed clonal expansion of Vδ1 and Vδ3 clonotypes, and functional studies using cloned γδ TCRs demonstrated restriction of these for CD1c and MR1 antigen-presenting molecules. On the basis of a 13-gene γδ T–cell signature derived from scRNA-seq analysis, gene-set enrichment on bulk RNA-seq data showed a positive correlation between enrichment scores and DN T-cell infiltrates. An improved disease-specific survival was evident for patients with high enrichment scores, and complete responses to anti–PD-1/PD-L1 treatment were observed in three of four cases with high enrichment scores. Thus, γδ T–cell infiltration may serve as a prognostic biomarker and should be explored for therapeutic interventions.See related Spotlight on p. 600

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