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Tissue-resident memory T cells are epigenetically cytotoxic with signs of exhaustion in human urinary bladder cancer
Karolinska Inst, Sweden.
Karolinska Inst, Sweden.
Karolinska Inst, Sweden.
Karolinska Inst, Sweden.
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2018 (English)In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 194, no 1, p. 39-53Article in journal (Refereed) Published
Abstract [en]

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 (32amp;lt;boldamp;gt;amp;lt;/boldamp;gt;9% 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.

Place, publisher, year, edition, pages
WILEY , 2018. Vol. 194, no 1, p. 39-53
Keywords [en]
CD8-positive T lymphocytes; cell exhaustion; DNA methylation; perforin; tissue-resident memory T cells; urinary bladder neoplasms
National Category
Immunology
Identifiers
URN: urn:nbn:se:liu:diva-151934DOI: 10.1111/cei.13183ISI: 000445601500005PubMedID: 30009527OAI: oai:DiVA.org:liu-151934DiVA, id: diva2:1259515
Note

Funding Agencies|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

Available from: 2018-10-30 Created: 2018-10-30 Last updated: 2019-04-12

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Huge, YlvaAljabery, Firas
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Department of Clinical and Experimental MedicineFaculty of Medicine and Health SciencesDepartment of Urology in Östergötland
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