Pseudotime dynamics of T cells in pancreatic ductal adenocarcinoma inform distinct functional states within the regulatory and cytotoxic T cells

Ashwin Jainarayanan; Nithishwer Mouroug-Anand; Edward H Arbe-Barnes; Adam J Bush; Rachael Bashford-Rogers; Adam Frampton; Lara Heij; Mark Middleton; Michael L Dustin; Enas Abu-Shah; Shivan Sivakumar

doi:10.1016/j.isci.2023.106324

Pseudotime dynamics of T cells in pancreatic ductal adenocarcinoma inform distinct functional states within the regulatory and cytotoxic T cells

iScience. 2023 Mar 7;26(4):106324. doi: 10.1016/j.isci.2023.106324. eCollection 2023 Apr 21.

Authors

Ashwin Jainarayanan^{1

2}, Nithishwer Mouroug-Anand³, Edward H Arbe-Barnes⁴, Adam J Bush⁴, Rachael Bashford-Rogers⁵, Adam Frampton⁶, Lara Heij⁷, Mark Middleton⁸, Michael L Dustin¹, Enas Abu-Shah^{1

9}, Shivan Sivakumar^{1

8}

Affiliations

¹ Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, OX3 7FY Oxford, UK.
² Interdisciplinary Bioscience Doctoral Training Centre, University of Oxford, OX1 3NP Oxford, UK.
³ Department of Biochemistry, University of Oxford, OX1 3QU Oxford, UK.
⁴ University of Oxford Medical School, OX3 9DU Oxford, UK.
⁵ Wellcome Trust Centre for Human Genetics, University of Oxford, OX3 7BN Oxford, UK.
⁶ Department of Surgery, University of Surrey, Surrey, GU2 7XH Guildford, UK.
⁷ Department of Pathology, University of Aachen, 52062 Aachen, Germany.
⁸ Department of Oncology, University of Oxford, OX3 7DQ Oxford, UK.
⁹ Sir William Dunn School of Pathology, University of Oxford, OX1 3RE Oxford, UK.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest types of cancer and has a 5-year survival of less than 8% owing to its complex biology. As PDAC is refractory to immunotherapy, we need to understand the functional dynamics of T cells in the PDAC microenvironment to develop alternative therapeutic strategies. In this study, we performed RNA velocity-based pseudotime analysis on a scRNA-seq dataset from surgically resected human PDAC specimens to gain insight into temporal gene expression patterns that best characterize the cell fates. The tumor microenvironment was seen to encompass a range of terminal states for the T cell trajectories with suppressive and non-tumor-responsive T cells dominating them. However, the results also reveal the existence of a functional branch of the T cell population that was not transitioning to exhausted and senescent states. These findings reveal various microenvironmental signals driving T cell patterns which can be useful in identifying new therapeutic avenues.

Keywords: Bioinformatics; Cancer systems biology; Immune response.

Grants and funding

BB/M011224/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom