LAUSR

Pancreatic ductal adenocarcinoma (PDA) tumors have a highly immunosuppressive desmoplastic tumor microenvironment (TME) where immune checkpoint inhibition (ICI) therapy has been exceptionally ineffective. Transforming growth factor‐β (TGF‐β) receptor activation leads to cancer and immune cell proliferation and phenotype, and cytokine production leading to tumor progression and worse overall survival in PDA patients. We hypothesized that TGF‐β receptor inhibition may alter PDA progression and antitumor immunity in the TME. Here, we used a syngeneic preclinical murine model of PDA to explore the impact of TGF‐β pathway inhibitor galunisertib (GAL), dual checkpoint immunotherapy (anti‐PD‐L1 and CTLA‐4), the chemotherapy gemcitabine (GEM), and their combinations on antitumor immune responses. Blockade of TGF‐β and ICI in immune‐competent mice bearing orthotopically injected murine PDA cells significantly inhibited tumor growth and was accompanied by antitumor M1 macrophage infiltration. In contrast, GEM treatment resulted in increased PDA tumor growth, decreased antitumor M1 macrophages, and decreased cytotoxic CD8+ T cell subpopulation compared to control mice. Together, these findings demonstrate the ability of TGF‐β inhibition with GAL to prime antitumor immunity in the TME and the curative potential of combining GAL with dual ICI. These preclinical results indicate that targeted inhibition of TGF‐β may enhance the efficacy of dual immunotherapy in PDA. Optimal manipulation of the immune TME with non‐ICI therapy may enhance therapeutic efficacy.