Tumor-educated B cells selectively promote breast cancer lymph node metastasis by HSPA4-targeting IgG

• Published in: Nature medicine Vol. 25; no. 2; pp. 312 - 322
• Main Authors: Gu, Yan, Liu, Yanfang, Fu, Li, Zhai, Lili, Zhu, Jie, Han, Yanmei, Jiang, Yingming, Zhang, Yi, Zhang, Peng, Jiang, Zhengping, Zhang, Xiang, Cao, Xuetao
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.02.2019; Nature Publishing Group
• Subjects: 631/250; 631/250/580; 631/67/322; 692/699/67/1347; Animals; Antibodies; B cells; B-Lymphocytes - immunology; Binding proteins; Biomedical and Life Sciences; Biomedicine; Breast cancer; Breast Neoplasms - blood; Breast Neoplasms - pathology; Cancer; Cancer cells; Cancer metastasis; Cancer Research; Care and treatment; Cell Line, Tumor; Chemokine CXCL12 - metabolism; CXCR4 protein; Development and progression; Glycosylation; Health aspects; HSP110 Heat-Shock Proteins - metabolism; Humans; Humoral immunity; Immunity; Immunoglobulin G; Immunoglobulin G - blood; Immunoglobulin G - metabolism; Infectious Diseases; Laboratory rats; Lymph nodes; Lymph Nodes - pathology; Lymphatic Metastasis - pathology; Lymphatic system; Lymphocytes B; Membrane proteins; Metabolic Diseases; Metastases; Metastasis; Mice; Molecular Medicine; Neurosciences; NF-kappa B - metabolism; NF-κB protein; Organs; Prognosis; Protein Binding; Proteins; Receptors, CXCR4; Signal Transduction; Tumor cells; Tumors
• ISSN: 1078-8956; 1546-170X; 1546-170X
• DOI: 10.1038/s41591-018-0309-y

Primary tumors may create the premetastatic niche in secondary organs for subsequent metastasis. Humoral immunity contributes to the progression of certain cancers, but the roles of B cells and their derived antibodies in premetastatic niche formation are poorly defined. Using a mouse model of spontaneous lymph node metastasis of breast cancer, we show that primary tumors induced B cell accumulation in draining lymph nodes. These B cells selectively promoted lymph node metastasis by producing pathogenic IgG that targeted glycosylated membrane protein HSPA4, and activated the HSPA4-binding protein ITGB5 and the downstream Src/NF-κB pathway in tumor cells for CXCR4/SDF1α-axis-mediated metastasis. High serum anti-HSPA4 IgG was correlated with high tumor HSPA4 expression and poor prognosis of breast cancer subjects. Our findings identify a key role for tumor-educated B cells and their derived antibodies in lymph node premetastatic niche formation, providing potential targets for cancer intervention. B cells facilitate breast cancer metastasis to lymph nodes through production of antibodies targeting a protein on the surface of cancer cells that stimulates tumor dissemination.