MHCII+ cancer-associated fibroblasts promote antitumor immunity in pancreatic cancer

The functions of major histocompatibility complex class II molecule-expressing cancer-associated fibroblasts (MHCII+CAFs) in pancreatic cancer remain controversial. MHCII+CAFs are primarily described as immunosuppressive, as MHCII allows for direct interaction with, and support of, regulatory T cells (Tregs). However, MHCII+CAF functions may be more complex depending on their origins and their cellular interactions within the tumor microenvironment. Here, using orthotopic models of pancreatic cancer, we show that conventional CD4+ T cells and their production of Interferon gamma (IFNγ) increased MHCII+CAFs in tumors. Acute depletion of Tregs using Foxp3DTR mice revealed that Tregs suppress the abundance of MHCII+CAFs in tumors by inhibiting CD4 T cell responses that can directly control primary tumor growth and metastatic progression. Functionally, MHCII expression on fibroblasts was required for CD4 T cell control of PDAC progression upon Treg ablation. Collectively, our findings identify an IFNγ-driven, antitumor activity of MHCII expression on CAFs and reveal that CAFs may be harnessed to promote adaptive immunity to PDAC.