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
Affiliations
Ashwin Jainarayanan
Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, OX3 7FY Oxford, UK; Interdisciplinary Bioscience Doctoral Training Centre, University of Oxford, OX1 3NP Oxford, UK
Nithishwer Mouroug-Anand
Department of Biochemistry, University of Oxford, OX1 3QU Oxford, UK
Edward H. Arbe-Barnes
University of Oxford Medical School, OX3 9DU Oxford, UK
Adam J. Bush
University of Oxford Medical School, OX3 9DU Oxford, UK
Rachael Bashford-Rogers
Wellcome Trust Centre for Human Genetics, University of Oxford, OX3 7BN Oxford, UK
Adam Frampton
Department of Surgery, University of Surrey, Surrey, GU2 7XH Guildford, UK
Lara Heij
Department of Pathology, University of Aachen, 52062 Aachen, Germany
Mark Middleton
Department of Oncology, University of Oxford, OX3 7DQ Oxford, UK
Michael L. Dustin
Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, OX3 7FY Oxford, UK
Enas Abu-Shah
Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, OX3 7FY Oxford, UK; Sir William Dunn School of Pathology, University of Oxford, OX1 3RE Oxford, UK; Corresponding author
Shivan Sivakumar
Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, OX3 7FY Oxford, UK; Department of Oncology, University of Oxford, OX3 7DQ Oxford, UK; Corresponding author
Summary: 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.
