Background Macrophages play a critical role in tumor growth, immunosuppression, and inhibition of adaptive immune responses in cancer. Hence, targeting signaling pathways in macrophages that promote tumor immunosuppression will provide therapeutic benefits.

Methods Myeloid Syk KO mice, B cell Syk KO mice, LLC, B16 melanoma, NB9464 neuroblastoma, and murine KPC1245 pancreatic adenocarcinoma cell lines were used to elucidate the effect of myeloid Syk on the tumor microenvironment (TME). In addition, the effect of Syk inhibitor, R788, on anti-tumor immunity alone or in combination with immunotherapy or chemotherapy was also determined in various tumor models.

Results We found that Syk promotes immunosuppressive transcriptional programming in tumor-associated macrophages (TAMs) that promotes tumor growth and metastasis. Syk controls stabilization of hypoxia-inducible factor (HIF1/2α) to promote immunosuppression during tumor growth, while genetic deletion of this kinase or use of FDA-approved Syk inhibitor R788 (aka, fostamatinib), activates NFκB signaling, increases the expression of Il12, Ifng, and Nos2 and skews the macrophages toward an immunostimulatory phenotype in vitro and in vivo. ^1–3 This reprogramming of macrophages towards an immunostimulatory phenotype in Syk-inhibitor-treated 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.^1–3

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.

Acknowledgements This work was supported by NIH grants K22 CA229594, R01NS122835 to Shweta Joshi.

References

1. Joshi S, Liu KX, Zulcic M, Singh AR, Skola D, Glass CK, et al. Macrophage Syk-PI3Kgamma Inhibits Antitumor Immunity: SRX3207, a Novel Dual Syk-PI3K Inhibitory Chemotype Relieves Tumor Immunosuppression. Mol Cancer Ther 2020;19:755–64

2. Rohila D PI, Pham T, Jones R, Tapia E, Liu KX, Tamayo P, Yu A, Sharabi A, Joshi S. Targeting macrophage Syk enhances responses to immune checkpoint blockade and radiotherapy in high-risk neuroblastoma. Frontiers in Immunology 2023

3. Rohila D PI, Pham TV, Weitz J, Mendoza T, Madheswaran S, Ishfaq M, Beaman C, Tapia E, Sun S, Patel J, Tamayo P, Lowy AM, Joshi S. Syk inhibition reprograms tumor-associated macrophages and overcomes gemcitabine-induced immunosuppression in pancreatic ductal adenocarcinoma. Cancer Research 2023

Ethics Approval Human tissues from deidentified patient samples were received from UC San Diego Moores Cancer Center Biorepository under IRB-approved protocol #181755.