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Activated Regulatory T-Cells, Dysfunctional and Senescent T-Cells Hinder the Immunity in Pancreatic Cancer

Authors: Sivakumar, Shivan; Abu-Shah, Enas; Ahern, David J.; Arbe-Barnes, Edward H.; Jainarayanan, Ashwin K.; Mangal, Nagina; Reddy, Srikanth; Rendek, Aniko; Easton, Alistair; Kurz, Elke; Silva, Michael; Soonawalla, Zahir; Heij, Lara R.; Bashford-Rogers, Rachael; Middleton, Mark R.; Dustin, Michael L.

Online: https://www.mdpi.com/2072-6694/13/8/1776

Issue: Cancers (Basel). 2021 Apr 8;13(8):1776.


Pancreatic cancer has one of the worst prognoses of any human malignancy and leukocyte infiltration is a major prognostic marker of the disease. As current immunotherapies confer negligible survival benefits, there is a need to better characterise leukocytes in pancreatic cancer to identify better therapeutic strategies. In this study, we analysed 32 human pancreatic cancer patients from two independent cohorts. A multi-parameter mass-cytometry analysis was performed on 32,000 T-cells from eight patients. Single-cell RNA sequencing dataset analysis was performed on a cohort of 24 patients. Multiplex immunohistochemistry imaging and spatial analysis were performed to map immune infiltration into the tumour microenvironment. Regulatory T-cell populations demonstrated highly immunosuppressive states with high TIGIT, ICOS and CD39 expression. CD8+ T-cells were found to be either in senescence or an exhausted state. The exhausted CD8 T-cells had low PD-1 expression but high TIGIT and CD39 expression. These findings were corroborated in an independent pancreatic cancer single-cell RNA dataset. These data suggest that T-cells are major players in the suppressive microenvironment of pancreatic cancer. Our work identifies multiple novel therapeutic targets that should form the basis for rational design of a new generation of clinical trials in pancreatic ductal adenocarcinoma.