Abstract 2577: Antigen-presenting CAFs in PDAC differentially regulate Treg phenotype and function via CXCL9 and CCL22
Authors: Saumya Y. Maru, Jacob T. Mitchell, Meredith Wetzel, Nicole E. Gross, Lalitya Andaloori, Kathryn Howe, Emma Kartalia, Guanglan Mo, James Leatherman, Won Jin Ho, Elana Fertig, Luciane T. Kagohara, Edward J. Pearce, Elizabeth M. Jaffee
Journal: Cancer Research (2025)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is characterized by a complex tumor microenvironment (TME) including stromal cells that influence resistance to therapy. Recent studies have revealed that stromal cancer-associated fibroblasts (CAFs) are heterogeneous in origin, gene expression, and function. One such population, antigen-presenting CAFs (apCAFs), is defined by MHC-II and can induce both CD4+ T cell activation and regulatory T cell (Treg) differentiation. Understanding apCAF biology could uncover mechanisms that can be targeted to promote CAF differentiation and enhance T cell activity. Methods: Two clones differing in sensitivity to immune checkpoint blockade (ICB), derived from the autochthonous KPC murine PDAC model, were implanted orthotopically into the pancreas of syngeneic C57BL/6 mice. apCAF KO mice were generated by crossing PDGFRαCre and MHC-IIflx mice. All mouse strains were untreated, treated with ICB or anti-mesothelin antibody, or immunized with a KRAS peptide vaccine. Tumors were harvested for TME characterization, functional assays, single-cell RNA sequencing (scRNAseq), and imaging mass cytometry (IMC). apCAFs, DCs, and CD4+ T cells were isolated and peptide-pulsed apCAFs and DCs were cultured with naïve OT-II CD4+ T cells or tumor-infiltrating CD4+ T cells. Cell to cell communication inference using dominoSignal was performed to assess signaling between apCAFs and CD4+ T cells. Results: Immunosensitive (sKPC) tumors were characterized by higher immune cell and apCAF infiltration than resistant (rKPC) tumors. IMC analysis showed proximity of apCAFs and CD4+ T cells in both sKPC and rKPC tumors implicating interaction within the TME. apCAF-depleted sKPC tumor-bearing mice have diminished sensitivity to ICB. apCAFs activate tumor-infiltrating CD4+ T cells and induce Treg differentiation, but not production of immunosuppressive cytokines in sKPC tumors. scRNAseq revealed greater Th1-like Treg differentiation in CD4s cultured with sKPC apCAFs, and differential chemokine signaling from apCAFs based on TME of origin, such that sKPC apCAFs induce Th1-like Tregs via CXCL9 and rKPC apCAFs induce classical Tregs via CCL22. Conclusions: apCAFs are more abundant in immunosensitive PDAC tumors, spatially involved with CD4+ T cells, and are functionally relevant for response to ICB as shown by two depletion models. Notably, chemokine signaling from apCAFs varies with tumor of origin and modulates Treg function. Together these data implicate apCAFs as important mediators of the antitumor immune response. Although a small proportion of the TME, modulating apCAF number or function may provide a solution to the currently unmet need of new and more effective treatments for PDAC patients. Citation Format: Saumya Y. Maru, Jacob T. Mitchell, Meredith Wetzel, Nicole E. Gross, Lalitya Andaloori, Kathryn Howe, Emma Kartalia, Guanglan Mo, James Leatherman, Won Jin Ho, Elana Fertig, Luciane T. Kagohara, Edward J. Pearce, Elizabeth M. Jaffee. Antigen-presenting CAFs in PDAC differentially regulate Treg phenotype and function via CXCL9 and CCL22. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2577.