Attenuation of Sialylation Augments Antitumor Immunity and Improves Response to Immunotherapy in Ovarian Cancer

Abstract Aberrant sialylation functions as an important modulator of all steps of malignant transformation. Therefore, targeting sialylation regulators, such as sialyltransferases and neuraminidases, is a potential strategy for treating cancer. Here, we found that elevated α2,3-sialyltransferase III (St3gal3) was associated with dismal prognosis in high-grade serous ovarian carcinoma (HGSC). St3gal3 knockdown antagonized subcutaneous tumor growth in immunocompetent, but not immunodeficient mice, with enhanced accumulation of functional CD8+ T cells and antitumor immune gene signatures. St3gal3 knockdown inhibited intraperitoneal tumor growth and repolarized tumor-associated macrophages from a protumorigenic M2-like to a tumor-suppressive M1-like phenotype. In vitro, St3gal3 knockdown tumor cells guided bone marrow–derived macrophages (BMDM) toward the M1-like phenotype under both direct contact and distant Transwell coculture conditions. Depletion of macrophages rescued the suppressed tumor growth induced by St3gal3 knockdown and completely suppressed infiltration of functional CD8+ T cells that rely on macrophage-derived CXCL10. St3gal3 engendered an immunosuppressive HGSC microenvironment characterized by an abundance of pro-tumorigenic macrophages and reduced cytotoxic T-cell infiltration. In vivo, St3gal3 knockdown improved effectiveness of dual immune checkpoint blockade (ICB) with αPD-1 and αCTLA4 antibodies. Preclinical inhibition of sialylation with ambroxol resulted in decreased tumor growth and prolonged the survival of tumor-bearing mice, which was enhanced by the addition of dual ICB. These findings indicate that altered sialylation induced by St3gal3 upregulation promotes a tumor-suppressive microenvironment in HGSC and targeting α2,3-sialylation may reprogram the immunosuppressive tumor microenvironment and improve the efficacy of immunotherapy. Significance: Blocking sialylation augments antitumor immunity and enhances response to immune checkpoint blockade therapy, highlighting a potential therapeutic approach for treating patients with high-grade serous ovarian cancer.