Immune responses in pancreatic cancer may be restricted by prevalence of activated regulatory T-cells, dysfunctional and senescent T-cells


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Shivan Sivakumar1, Enas Abu-Shah, David Ahern, Edward Arbe-Barnes, Nagina Mangal, Srikanth Reddy, Aniko Rendek, Alistair Easton, Elke Kurz, Michael Silva, Zahir Soonawalla, Lara Heij, Rachael Bashford-Rogers, Mark Middleton, Michael Dustin
1University of Oxford

Abstract

Background

Pancreatic cancer has the worst prognosis of any human malignancy and leukocyte infiltration appears to be 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. 

Method

In this study, a T cell focused CyTOF panel was used to analyse 32,000 T-cells from eight human pancreatic cancer patients. The results were validated using a publicly available pancreatic cancer single cell data set. T cell localisation was demonstrated using multiplexed immunofluorescence on human samples. 


  

Results

The T cell focused CyTOF panel revealed novel characteristics. Regulatory T-cell populations manifested a highly immunosuppressive state with high TIGIT, ICOS and CD39 expression. CD8+ T-cells were either senescent or exhausted, albeit with low PD-1 expression. These findings were corroborated in an independent pancreatic cancer single-cell RNA dataset from 24 patients. The multiplex immunofluorescence showed the regulatory T-cells were exclusively found in the stroma.



Conclusion

These data suggest that T-cells are major players in the suppressive microenvironment of pancreatic cancer, contributing to its poor prognosis. Our work identifies novel therapeutic targets that should form the basis for rational design of a new generation of clinical trials in PDAC.

Impact statement

Our findings indicate that for future immunotherapy studies in pancreatic cancer, inhibition of TIGIT or ICOS may be a more viable strategy then PD1.