Activated regulatory T-cells, dysfunctional and senescent T-cells hinder the immunity in pancreatic cancer

Journal article

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.

Authors: Sivakumar, S; Abu-Shah, E; Ahern, DJ; Arbe-Barnes, EH; Jainarayanan, AK

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: MDPI
• Journal: Cancers
• Volume: 13
• Issue: 8
• Article number: 1776
• Publication date: 2021-04-08
• Acceptance date: 2021-03-29
• DOI: 10.3390/cancers13081776
• EISSN: 2072-6694
• Language: English
• Keywords: immune checkpoints; ICOS; CD39; FFR; TIGIT; regulatory T-cells; pancreatic cancer; senescent T-cells