Huang et al. used scRNA sequencing and lineage tracing assays to determine the origin and functions of MHC-II+ antigen-presenting cancer-associated fibroblasts (apCAFs) in pancreatic ductal adenocarcinoma (PDA). As PDA progressed, the IL1-α and TGFβ pathways were responsible for inducing mesothelial cell differentiation to apCAFs that could directly induce naive CD4+ T cells to form suppressive Tregs in an antigen-specific manner. In a tumor model, treatment with a blocking mesothelin mAb inhibited apCAF formation, resulting in decreased Treg numbers, increased percentage of CD8+ T cells, and significantly lower tumor weight.
Contributed by Katherine Turner
ABSTRACT: Recent studies have identified a unique cancer-associated fibroblast (CAF) population termed antigen-presenting CAFs (apCAFs), characterized by the expression of major histocompatibility complex class II molecules, suggesting a function in regulating tumor immunity. Here, by integrating multiple single-cell RNA-sequencing studies and performing robust lineage-tracing assays, we find that apCAFs are derived from mesothelial cells. During pancreatic cancer progression, mesothelial cells form apCAFs by downregulating mesothelial features and gaining fibroblastic features, a process induced by interleukin-1 and transforming growth factor β. apCAFs directly ligate and induce naive CD4+ T cells into regulatory T cells (Tregs) in an antigen-specific manner. Moreover, treatment with an antibody targeting the mesothelial cell marker mesothelin can effectively inhibit mesothelial cell to apCAF transition and Treg formation induced by apCAFs. Taken together, our study elucidates how mesothelial cells may contribute to immune evasion in pancreatic cancer and provides insight on strategies to enhance cancer immune therapy.
Author Info: (1) Department of Surgery, University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd, Dallas, TX 75390, USA; Hamon Center for Therapeutic Oncology Research, University
Author Info: (1) Department of Surgery, University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd, Dallas, TX 75390, USA; Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd, Dallas, TX 75390, USA. Electronic address: huocong.huang@utsouthwestern.edu. (2) Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA 92093, USA. (3) Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd, Dallas, TX 75390, USA; Cancer Biology Graduate Program, University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd, Dallas, TX 75390, USA. (4) Genentech, South San Francisco, CA 94080, USA. (5) Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd, Dallas, TX 75390, USA; Cancer Biology Graduate Program, University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd, Dallas, TX 75390, USA. (6) Department of Surgery, University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd, Dallas, TX 75390, USA; Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd, Dallas, TX 75390, USA. (7) Department of Surgery, University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd, Dallas, TX 75390, USA; Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd, Dallas, TX 75390, USA. (8) Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd, Dallas, TX 75390, USA. (9) Department of Molecular Biology, University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd, Dallas, TX 75390, USA. (10) Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd, Dallas, TX 75390, USA; Department of Internal Medicine, University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd, Dallas, TX 75390, USA. (11) Genentech, South San Francisco, CA 94080, USA. (12) Genentech, South San Francisco, CA 94080, USA. (13) Department of Surgery, University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd, Dallas, TX 75390, USA; Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd, Dallas, TX 75390, USA; Cancer Biology Graduate Program, University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd, Dallas, TX 75390, USA; Department of Pharmacology, University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd, Dallas, TX 75390, USA. Electronic address: rolf.brekken@utsouthwestern.edu.
