Journal
CLINICAL AND EXPERIMENTAL IMMUNOLOGY
Volume 194, Issue 1, Pages 39-53Publisher
WILEY
DOI: 10.1111/cei.13183
Keywords
CD8-positive T lymphocytes; cell exhaustion; DNA methylation; perforin; tissue-resident memory T cells; urinary bladder neoplasms
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Funding
- Swedish Cancer Society (Cancerfonden)
- Regional Research Council in Uppsala-Orebro region, Sweden (RFR in Uppsala-Orebro)
- Swedish Research Council
- Cancer Research Foundation in Norrland, Umea, Sweden
- Stiftelsen Emil Anderssons fond for medicinsk forskning, Sundsvall, Sweden
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Tissue-resident memory T (T-RM) cells are CD8(+) T lymphocytes that reside in the tissues, including tumours. This T cell subset possesses a magnitude of cytotoxicity, but its epigenetic regulation has not been studied. Here, we investigate the impact of perforin DNA methylation in T-RM cells and correlate it with their functional potential. Fifty-three urothelial urinary bladder cancer (UBC) patients were recruited prospectively. The DNA methylation status of the perforin gene (PRF1) locus in T-RM cells was investigated by pyrosequencing. Flow cytometry with ViSNE analysis and in-vitro stimulation were used to evaluate T-RM cell phenotypes. We discovered that tumour T-RM cells have low DNA methylation in the PRF1 locus (329% methylation), which corresponds to increased numbers of perforin-expressing T-RM cells. Surprisingly, programmed cell death 1 (PD-1) expression is high in tumour T-RM cells, suggesting exhaustion. Following interleukin-15 and T cell receptor stimulation, perforin and T-bet expressions are enhanced, indicating that T-RM cells from tumours are not terminally exhausted. Moreover, a high number of T-RM cells infiltrating the tumours corresponds to lower tumour stage in patients. In conclusion, T-RM cells from UBC tumours are epigenetically cytotoxic with signs of exhaustion. This finding identifies T-RM cells as potential new targets for cancer immunotherapy.
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