Significance
The glycocalyx, a network of glycolipids and glycoproteins on cell surfaces, plays a pivotal role in immune modulation. Hypersialylated glycans have been identified as an immune suppressive marker, are exploited by tumors to evade immune recognition, and lead to suboptimal effectiveness of immune checkpoint blockade therapy in bone metastases. Here, we elaborated on the important roles of Siglec-15 in breast cancer bone metastases and bone microenvironment. We reported that Siglec-15/sialic acid axis represents as a glycoimmune checkpoint and modulator of tumor-induced osteoclastogenesis for bone cancers, and demonstrated that targeting the Siglec-15/sialic acid axis by anti-Siglec-15 antibody represents a promising approach for patients with breast cancer bone metastases.
Abstract
Immunotherapy is a promising approach for treating metastatic breast cancer (MBC), offering new possibilities for therapy. While checkpoint inhibitors have shown great progress in the treatment of metastatic breast cancer, their effectiveness in patients with bone metastases has been disappointing. This lack of efficacy seems to be specific to the bone environment, which exhibits immunosuppressive features. In this study, we elucidate the multiple roles of the sialic acid–binding Ig-like lectin (Siglec)-15/sialic acid glyco-immune checkpoint axis in the bone metastatic niche and explore potential therapeutic strategies targeting this glyco-immune checkpoint. Our research reveals that elevated levels of Siglec-15 in the bone metastatic niche can promote tumor-induced osteoclastogenesis as well as suppress antigen-specific T cell responses. Next, we demonstrate that antibody blockade of the Siglec-15/sialic acid glyco-immune checkpoint axis can act as a potential treatment for breast cancer bone metastasis. By targeting this pathway, we not only aim to treat bone metastasis but also inhibit the spread of metastatic cancer cells from bone lesions to other organs.
