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

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

doi:10.3390/cancers13081776

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

Cancers (Basel). 2021 Apr 8;13(8):1776. doi: 10.3390/cancers13081776.

Authors

Shivan Sivakumar^{1

2

3}, Enas Abu-Shah^{2

4}, David J Ahern², Edward H Arbe-Barnes⁵, Ashwin K Jainarayanan^{2

6}, Nagina Mangal⁷, Srikanth Reddy⁸, Aniko Rendek⁹, Alistair Easton¹, Elke Kurz², Michael Silva⁸, Zahir Soonawalla⁸, Lara R Heij^{10

11}, Rachael Bashford-Rogers¹², Mark R Middleton^{1

3

13}, Michael L Dustin²

Affiliations

¹ Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
² Kennedy Institute of Rheumatology, University of Oxford, Oxford OX3 7FY, UK.
³ Oncology, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 9DU, UK.
⁴ Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK.
⁵ University of Oxford Medical School, Oxford OX1 2JD, UK.
⁶ Interdisciplinary Bioscience Doctoral Training Program and Exeter College, University of Oxford, Oxford OX3 7DQ, UK.
⁷ Nuffield Department of Surgical Sciences, University of Oxford, Oxford OX3 9DU, UK.
⁸ Department of Surgery, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 9DU, UK.
⁹ Department of Pathology, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 9DU, UK.
¹⁰ Department of General, Gastrointestinal, Hepatobiliary and Transplant Surgery, RWTH Aachen University Hospital, 52074 Aachen, Germany.
¹¹ Institute of Pathology, University Hospital RWTH Aachen, 52074 Aachen, Germany.
¹² Wellcome Trust Centre for Human Genomics, University of Oxford, Oxford OX3 7BN, UK.
¹³ Oxford NIHR Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 9DU, UK.

Abstract

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.

Keywords: CD39; ICOS; TIGIT; immune checkpoints; pancreatic cancer; regulatory T-cells; senescent T-cells.

Abstract

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