Abstract Myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) are major negative regulators of anti-tumor immunity. Identifying tumor secreting factors and signaling pathways that enhance their pro-tumorigenic activity could lead to new strategies to enhance immunotherapy efficacy. We have identified tumor-secreted epidermal growth factor-like 6 (EGFL6) as a new mediator of tumor immune suppression. In-vitro and ex-vivo analyses indicated that EGFL6 binds beta integrins to activate spleen tyrosine kinase (SYK) signaling, functioning as (i) a chemotactic factor for myeloid cell migration and (ii) a driver of their differentiation into immunosuppressive phenotypes. In syngeneic mouse models of ovarian cancer, EGFL6 expression promoted intra-tumoral accumulation of MDSCs and TAMs with high SYK, CXCL2, and IL-10 expression. In an immune ‘hot’ tumor model, EGFL6 completely abrogated the response to anti-PD-L1 therapy, whereas Egfl6 neutralization decreased the accumulation of tumor-infiltrating CD206+ TAMs and MDSCs and thereby restored the efficacy of a-PD-L1 therapy. Spatial transcriptomic datasets of human ovarian cancer tissues revealed strong correlation between tumor EGFL6 and myeloid cell SYK expression. Dual immunohistochemistry confirmed increased SYK+ macrophages in ovarian cancer compared to normal ovary. We therefore tested whether SYK inhibition could hinder EGFL6-induced signaling in myeloid cells and reprogram them from an immunosuppressive to an immunostimulatory phenotype. Treatment with the SYK inhibitor fostamatinib (R788) prolonged survival in Egfl6+/- ID8p53-/- tumor-bearing mice, reduced the number of intra-tumoral granulocytic MDSCs, and decreased VEGF, M-CSF, and CXCL5 levels in ascites. scRNA-seq revealed that SYK inhibition depleted specific CCL8+ TAM and CXCL2+ MDSC subsets, induced immunostimulatory myeloid cell populations, and reduced exhausted of TIGIT+CTL4+ CD8 T cells. These findings demonstrate that targeting the EGFL6-SYK axis, via EGFL6 blockade or SYK inhibition, can reprogram the ovarian tumor microenvironment to enhance anti-tumor immunity and restore responsiveness of “cold” tumors to immunotherapy. Citation Format: Sandra Cascio. Reprogramming tumor-associated myeloid cells to improve ovarian cancer therapies abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85 (18Suppl): Abstract nr IA014.
Sandra Cascio (Fri,) studied this question.