γδ T Cells in Merkel Cell Carcinomas Have a Proinflammatory Profile Prognostic of Patient Survival
Autor: | Atara Posner, Richard A. Scolyer, Anthony J. Gill, Paolo Deleso, Alex Caneborg, Margaret Chua, Fernando J. Rossello, Jeanette Raleigh, Luciano G. Martelotto, Rodney J. Hicks, Kerwin F. Shannon, Magnus Zethoven, Grant A. McArthur, Paul J Neeson, Dale I. Godfrey, Nicholas A Gherardin, Pasquale Petrone, Sergio M. Quiñones-Parra, Meredith L Johnston, Valerie Jakrot, Andrew D Pattison, Shiva Balachander, Juergen C. Becker, Shahneen Sandhu, Athena Hatzimihalis, Angela Hong, Alison Weppler, Richard W. Tothill, Annie Wong, Kelly Waldeck, James S. Wilmott, Peter M. Ferguson |
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Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
Adult CD4-Positive T-Lymphocytes Male Cancer Research LAG3 Skin Neoplasms T-Lymphocytes Immunology Inflammation Context (language use) Biology CD8-Positive T-Lymphocytes Immunofluorescence Proinflammatory cytokine Cell Line 03 medical and health sciences 0302 clinical medicine medicine Humans Immune Checkpoint Inhibitors Aged Aged 80 and over medicine.diagnostic_test T-cell receptor Computational Biology Receptors Antigen T-Cell gamma-delta Middle Aged Prognosis Survival Analysis 3. Good health Carcinoma Merkel Cell 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis Cancer research Female medicine.symptom Merkel cell CD8 Biomarkers |
Zdroj: | Cancer immunology research. 9(6) |
ISSN: | 2326-6074 |
Popis: | 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 |
Databáze: | OpenAIRE |
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