Impact of SYK inhibition on the Ovarian Cancer Tumor Microenvironment 2250554

Abstract

Abstract Introduction Ovarian Cancer (OvCa) is an aggressive malignancy with poor survival outcomes, driven in part by an immunosuppressive tumor microenvironment (TME). Tumor-associated neutrophils (TANs) and macrophages (TAMs) promote immune tolerance and resistance to immunotherapy, limiting treatment efficacy. We recently identified tumor-secreted epidermal growth factor-like 6 (EGFL6) as a promoter of an immunosuppressive phenotype and inducer of spleen tyrosine kinase (SYK) signaling in infiltrating myeloid cells. In this study, we investigate the impact of SYK inhibitor R788 on OvCa tumor progression and whether SYK inhibition could reverse Egfl6-dependent immunosuppressive state in myeloid cells. Methods OvCa patient tumors were assessed to determine the correlation between EGFL6 and SYK expression in myeloid cells. A syngeneic mouse model of Egfl6 +/- OvCa cells was used to elucidate the effect of SYK inhibition on tumor progression and the immune TME. In addition, the effect of R788 on anti-tumor immunity alone or in combination with Paclitaxel was also determined. Results R788 (fostamatinib) reduced the proliferation of OvCa cells, as well as myeloid cells, in a dose-dependent manner. In vivo experiments showed that administration of R788 significantly improved the survival rate and reduced ascites volume in both control and Egfl6-overexpressing tumors, and combination of R788 along with Paclitaxel provided a synergistic effect in Egfl6+ tumors. We found that R788 decreased the number of TANs and reduced VEGF, M-CSF, and CXCL5 levels in ascites. Moreover, single-cell RNA-sequencing revealed that R788 drastically reprogrammed the immune TME, with SYK inhibition associated with a) depletion of specific CCL8+ TAMs and CXCL2+ TANs; and b) reduced number of exhausted TIGIT+CTL4+ CD8 T cells. Conclusion Our findings establish the role of an EGFL6-SYK regulatory axis in OvCa progression and identify SYK inhibitor R788 as a promising therapeutic agent to induce an anti-tumor immune response in OvCa patients. Funding Source NIH-National Cancer Institute Grant R01CA276279 (awarded to S.C.) Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)