Syk Inhibition Reprograms Tumor-Associated Macrophages and Overcomes Gemcitabine-Induced Immunosuppression in Pancreatic Ductal Adenocarcinoma

Abstract

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.

Nanoparticles in tumor microenvironment remodeling and cancer immunotherapy

“…A growing body of evidence supports the potential involvement of tumor-associated macrophages in the development of drug resistance [ 257 , 258 ]. These macrophages play a role beyond immune system regulation, influencing the response to chemotherapy.…”

The Pivotal Role of Macrophages in the Pathogenesis of Pancreatic Diseases

“…Furthermore, the role of spleen tyrosine kinase (Syk) has been shown to promote PDAC growth and metastasis [ 89 ]. The inhibition of Syk using specific chemicals like R788, a Syk inhibitor, exhibits anticancer effects by affecting macrophage polarization [ 90 ].…”

983 Syk promotes macrophage immunosuppressive phenotype to suppress anti-tumor immunity

“…Syk controls stabilization of hypoxia-inducible factor (HIF1/2a) to promote immunosuppression during tumor growth, while genetic deletion of this kinase or use of FDA-approved Syk inhibitor R788 (aka, fostamatinib), activates NFkB signaling, increases the expression of Il12, Ifng, and Nos2 and skews the macrophages toward an immunostimulatory phenotype in vitro and in vivo. [1][2][3] This reprogramming of macrophages towards an immunostimulatory phenotype in Syk-inhibitortreated tumors was accompanied by increased CD8+ T cell recruitment, enhanced CD8+ T cell proliferation, increased T cell expression of Ifng, Gzm, and Prf and bolstered CD8+ T cell responses in the solid tumors. [1][2][3] Conclusions Syk inhibitors either alone or together with immunotherapy or chemotherapy demonstrate efficacy in multiple tumor models and represent a novel combinatorial approach to activate antitumor immunity.…”

“…[1][2][3] This reprogramming of macrophages towards an immunostimulatory phenotype in Syk-inhibitortreated tumors was accompanied by increased CD8+ T cell recruitment, enhanced CD8+ T cell proliferation, increased T cell expression of Ifng, Gzm, and Prf and bolstered CD8+ T cell responses in the solid tumors. [1][2][3] Conclusions Syk inhibitors either alone or together with immunotherapy or chemotherapy demonstrate efficacy in multiple tumor models and represent a novel combinatorial approach to activate antitumor immunity.…”