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

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 Tcells 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 Tcell trajectories with suppressive and non-tumor-responsive Tcells dominating them. However, the results also reveal the existence of a functional branch of the Tcell population that was not transitioning to exhausted and senescent states. These findings reveal various microenvironmental signals driving Tcell patterns which can be useful in identifying new therapeutic avenues.