γδ T Cells in Merkel Cell Carcinomas Have a Proinflammatory Profile Prognostic of Patient Survival.
Nicholas A GherardinKelly WaldeckAlex CaneborgLuciano G MartelottoShiva BalachanderMagnus ZethovenPasquale M PetroneAndrew PattisonJames S WilmottSergio M Quiñones-ParraFernando RosselloAtara PosnerAnnie N M WongAlison M WepplerKerwin F ShannonAngela HongPeter M FergusonValerie JakrotJeanette RaleighAthena HatzimihalisPaul J NeesonPaolo DelesoMeredith JohnstonMargaret ChuaJürgen Christian BeckerShahneen SandhuGrant A McArthurAnthony J GillRichard A ScolyerRodney John HicksDale I GodfreyRichard W TothillPublished in: Cancer immunology research (2021)
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.
Keyphrases
- single cell
- rna seq
- high throughput
- end stage renal disease
- case report
- genome wide
- oxidative stress
- induced apoptosis
- gene expression
- high grade
- ejection fraction
- chronic kidney disease
- crispr cas
- newly diagnosed
- nk cells
- physical activity
- magnetic resonance imaging
- copy number
- immune response
- peritoneal dialysis
- dna methylation
- regulatory t cells
- big data
- genome wide identification
- prognostic factors
- artificial intelligence
- patient reported
- heat shock protein