RT Journal Article
SR Electronic
T1 Immune responses in pancreatic cancer may be restricted by prevalence of activated regulatory T-cells, dysfunctional and senescent T-cells
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.06.20.163071
DO 10.1101/2020.06.20.163071
A1 Shivan Sivakumar
A1 Enas Abu-Shah
A1 David J Ahern
A1 Edward H Arbe-Barnes
A1 Nagina Mangal
A1 Srikanth Reddy
A1 Aniko Rendek
A1 Alistair Easton
A1 Elke Kurz
A1 Michael Silva
A1 Zahir Soonawalla
A1 Lara R Heij
A1 Rachael Bashford-Rogers
A1 Mark R Middleton
A1 Michael L Dustin
YR 2020
UL http://biorxiv.org/content/early/2020/11/11/2020.06.20.163071.abstract
AB Objective Pancreatic cancer has the worst prognosis 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.Design In this study, a multi-parameter mass-cytometry analysis was performed on 32,000 T-cells from eight human pancreatic cancer 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.Results 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 from 24 patients.Conclusions These data suggest that T-cells are major players in the suppressive microenvironment of pancreatic cancer. Our work identifies novel therapeutic targets that should form the basis for rational design of a new generation of clinical trials in pancreatic ductal adenocarcinoma.Statement of Significance This study elucidates the T-cell phenotypes in pancreatic ductal adenocarcinoma (PDAC). T-cells potentiate immune-suppression through an activated regulatory T-cell population expressing high TIGIT, ICOS and CD39. CD8+ T-cells were primarily senescent or TIGIT+ exhausted, but with minimal PD-1 expression. These findings propose new immunotherapy targets for PDAC.Competing Interest StatementSS has salary and research expenses from BMS. EAS has salary from UCB. RJMB-R is a co-founder and consultant for Alchemab Therapeutics Ltd and a consultant for Imperial College London and VHSquared. MM reports personal fees from Amgen, grants and personal fees from Roche, grants from Astrazeneca, grants and personal fees from GSK, personal fees and other from Novartis, other from Millenium, personal fees, non-financial support and other from Immunocore, personal fees and other from BMS, personal fees and other from Eisai, other from Pfizer, personal fees, non-financial support and other from Merck/MSD, personal fees and other from Rigontec (acquired by MSD), other from Regeneron, personal fees from BiolineRx, personal fees and other from Array Biopharma (now Pfizer), non-financial support and other from Replimune, personal fees from Kineta, personal fees from Silicon Therapeutics, outside the submitted work.