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
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 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 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.
Background Lead is an important environmental and occupational pollutant and it can cause nephrotoxicity even at low doses. Early detection of renal disease from occupational and environmental exposure to nephrotoxic chemicals is currently limited by the lack of sensitive or chemical specific tests. There are growing body of evidence that supports Kidney injury molecule-1 (KIM-1) as a specific marker for nephrotoxicity, specificallyischemic renal injury. δaminolevulinic acid dehydratase (ALAD) gene polymorphism is known as an important factor affecting workers susceptibility to lead toxicity, further role of ALAD-1-1 and ALAD2-2 genotype is not clear yet. Correlation among the blood lead level, ALAD genotype present, urinary KIM-1 level of workers can provide better understanding about lead intoxication pattern and the role of genetic factor in susceptibility towards lead intoxication among workers.
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