Siglec-15/sialic acid axis as a central glyco-immune checkpoint in breast cancer bone metastasis

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....

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 121; no. 5; p. e2312929121
Main Authors Wang, Yixian, Xu, Zhan, Wu, Kuan-Lin, Yu, Liqun, Wang, Chenhang, Ding, Haoxue, Gao, Yang, Sun, Han, Wu, Yi-Hsuan, Xia, Meng, Chen, Yuda, Xiao, Han
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 30.01.2024
Subjects
Acids
Antibodies
Antibodies, Blocking
Biological Sciences
Bone cancer
Bone lesions
Bone Neoplasms - drug therapy
Breast cancer
Breast Neoplasms - drug therapy
Female
Humans
Immune checkpoint inhibitors
Immunoglobulins
Immunotherapy
Lymphocytes
Lymphocytes T
Metastases
Metastasis
N-Acetylneuraminic Acid
Osteoclastogenesis
Physical Sciences
glycocalyx
bone
Siglec
sialic acid
glycobiology
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Summary: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.
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1Y.W. and Z.X. contributed equally to this work.
Edited by Carolyn Bertozzi, Stanford University, Stanford, CA; received July 27, 2023; accepted December 6, 2023
ISSN:0027-8424
1091-6490
1091-6490
DOI:10.1073/pnas.2312929121