Single-Cell Sequencing Reveals Trajectory of Tumor-Infiltrating Lymphocyte States in Pancreatic Cancer

Authors

Aislyn Schalck
Donastas Sakellariou-Thompson
Marie-Andrée Forget
Emi Sei
Tara G Hughes
Alexandre Reuben
Shanshan Bai
Min Hu
Tapsi Kumar
Mark W Hurd
Matthew H G Katz
Ching-Wei D Tzeng
Shubham Pant
Milind Javle
David R Fogelman
Anirban Maitra
Cara L Haymaker
Michael P Kim
Nicholas E Navin
Chantale Bernatchez

Publication Date

10-5-2022

Journal

Cancer Discovery

Abstract

Pancreatic ductal adenocarcinoma (PDAC) has few effective treatments. Immunotherapy, an attractive alternative strategy, remains challenging with the lack of knowledge on the tumor-infiltrating lymphocyte (TIL) landscape in PDAC. To generate a reference of T-cell subpopulations, we profiled 80,000 T cells from 57 PDAC samples, 22 uninvolved/normal samples, and cultured TIL using single-cell transcriptomic and T-cell receptor analysis. These data revealed 20 cell states and heterogeneous distributions of TIL populations. The CD8+ TIL contained a putative transitional GZMK+ population based on T-cell receptor clonotype sharing, and cell-state trajectory analysis showed similarity to a GZMB+PRF1+ cytotoxic and a CXCL13+ dysfunctional population. Statistical analysis suggested that certain TIL states, such as dysfunctional and inhibitory populations, often occurred together. Finally, analysis of cultured TIL revealed that high-frequency clones from effector populations were preferentially expanded. These data provide a framework for understanding the PDAC TIL landscape for future TIL use in immunotherapy for PDAC.

Keywords

Carcinoma, Pancreatic Ductal, Humans, Lymphocytes, Tumor-Infiltrating, Pancreatic Neoplasms, Receptors, Antigen, T-Cell

Comments

Supplementary Material

PMID: 35849783

DOI

10.1158/2159-8290.CD-21-1248

PMID

35849783

PMCID

PMC9547957

PubMedCentral® Posted Date

April 2023

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes