Syk inhibition reprograms tumor-associated macrophages and overcomes gemcitabine-induced immunosuppression in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is an insidious disease with a low five-year survival rate. PDAC is characterized by infiltration of abundant tumor-associated macrophages (TAMs) that promote immune tolerance and immunotherapeutic resistance. Here we report that macrophage spleen tyrosine kinase (Syk) promotes PDAC growth and metastasis. In orthotopic PDAC mouse models, genetic deletion of myeloid Syk reprogrammed macrophages into immunostimulatory phenotype, increased the infiltration, proliferation, and cytotoxicity of CD8+ T cells, and repressed PDAC growth and metastasis. Furthermore, gemcitabine (Gem) treatment induced an immunosuppressive microenvironment in PDAC by promoting pro-tumorigenic polarization of macrophages. In contrast, treatment with the FDA-approved Syk inhibitor R788 (fostamatinib) remodeled the tumor immune microenvironment, "re-educated" pro-tumorigenic macrophages towards an immunostimulatory phenotype and boosted CD8+ T cell responses in Gem-treated PDAC in orthotopic mouse models and an ex vivo human pancreatic slice culture model. These findings illustrate the potential of Syk inhibition for enhancing the anti-tumor immune responses in PDAC and support the clinical evaluation of R788 either alone or together with Gem as a potential treatment strategy for PDAC.