Cross-Species Single-Cell Analysis of Pancreatic Ductal Adenocarcinoma Reveals Antigen-Presenting Cancer-Associated Fibroblasts

TLDR

Cancer‑associated fibroblasts drive pancreatic ductal adenocarcinoma progression and drug resistance, yet their heterogeneity remains poorly defined. We aimed to comprehensively map the cellular composition of human and mouse PDAC tumors using single‑cell RNA sequencing. Single‑cell transcriptomics was applied to dissect the neoplastic and tumor microenvironment compartments in these tumors. We identified distinct CAF subtypes in human and mouse PDAC, including a novel MHC class II–expressing antigen‑presenting CAF population that activates CD4⁺ T cells antigen‑specifically, underscoring the importance of CAF heterogeneity for tumor immunity and therapeutic targeting.

Abstract

Cancer-associated fibroblasts (CAF) are major players in the progression and drug resistance of pancreatic ductal adenocarcinoma (PDAC). CAFs constitute a diverse cell population consisting of several recently described subtypes, although the extent of CAF heterogeneity has remained undefined. Here we use single-cell RNA sequencing to thoroughly characterize the neoplastic and tumor microenvironment content of human and mouse PDAC tumors. We corroborate the presence of myofibroblastic CAFs and inflammatory CAFs and define their unique gene signatures in vivo. Moreover, we describe a new population of CAFs that express MHC class II and CD74, but do not express classic costimulatory molecules. We term this cell population "antigen-presenting CAFs" and find that they activate CD4+ T cells in an antigen-specific fashion in a model system, confirming their putative immune-modulatory capacity. Our cross-species analysis paves the way for investigating distinct functions of CAF subtypes in PDAC immunity and progression. SIGNIFICANCE: Appreciating the full spectrum of fibroblast heterogeneity in pancreatic ductal adenocarcinoma is crucial to developing therapies that specifically target tumor-promoting CAFs. This work identifies MHC class II-expressing CAFs with a capacity to present antigens to CD4+ T cells, and potentially to modulate the immune response in pancreatic tumors.See related commentary by Belle and DeNardo, p. 1001.This article is highlighted in the In This Issue feature, p. 983.