Tumor sialylation controls effective anti-cancer immunity in breast cancer

Abstract

Immunotherapies have revolutionized treatment and management of cancers. However, the use of immune checkpoint inhibitors (ICIs) in breast cancer is limited due to lack of efficacy. Sialylation, the modification of glycans with sialic acid, is frequently upregulated in various cancer types and has potent immunoregulatory properties. However, its specific role in breast cancer immune evasion has remained largely elusive. Here, we show that breast cancer sialylation drives the recruitment of polymorphonuclear myeloid suppressor cells to the tumor microenvironment, thus hampering the efficient eradication of tumors by CD8+ T cells. Notably, abrogation of tumor sialylation, either genetically or pharmacologically, not only facilitated CD8-mediated tumor control but also enabled the recruitment of Tcf7+ memory T cells. Significantly, abrogation of sialylation sensitized PD-1-resistant breast tumors to immunotherapy. Sialylation interference was well-tolerated in mammary development and function. We further demonstrate that hyper-sialylation occurs in over half of human breast cancers and correlates with poor T cell infiltration. Our results establish sialylation as a central immunoregulator in breast cancer, orchestrating multiple pathways that ultimately culminate in immune evasion. Importantly, our study underscores the potential of targeting this pathway to enhance tumor control, converting immunologically inert tumors into inflamed ones, and prime tumors for synergistic interventions involving immune checkpoint inhibitors.