B Cell–Derived Antibodies Promote Lymph Node Metastasis in Breast Cancer

Primary tumors support the generation of premetastatic niches by recruiting bone marrow–derived cells to secondary tissue sites and secreting factors that educate cells at these sites to establish an immunosuppressive microenvironment. B cells have been implicated in tumor growth and progression via inhibition of antitumor immune responses and production of tumor-promoting humoral immunity; however, the role of B cells and B cell–derived antibodies in the formation of the premetastatic niche remains unclear. In a mouse model of spontaneous breast cancer metastasis, Gu, Liu, and colleagues found that primary tumors stimulated the recruitment of B cells to draining lymph nodes (DLN). B cells from DLNs of tumor-bearing mice produced high levels of pathogenic IgG, which targeted tumor membrane antigens and increased breast cancer cell migration and invasion to selectively enhance lymph node metastasis. This prometastatic effect was mediated by binding of pathogenic IgG to glycosylated heat shock protein family A member 4 (HSPA4), a candidate tumor antigen of the HSP70 family, on the tumor-cell surface, leading to activation of the HSPA4-binding protein integrin β5 (ITGB5) and downstream induction of signaling via SRC kinase and the NFκB pathway. Activation of NFκB signaling was required for HIF1α-dependent induction of C-X-C motif chemokine receptor 4 (CXCR4) in tumor cells and cyclooxygenase 2 (COX2)–driven expression of the CXCR4 ligand stromal-derived factor 1α (SDF1α) in lymph node stromal cells. Pharmacologic inhibition of CXCR4 or COX2 or knockdown of HSPA4 or ITGB5 in tumor cells attenuated lymph node metastasis in tumor-bearing mice. In addition, high tumor HSPA4 expression and elevated serum levels of anti-HSPA4 IgG were associated with lymph node metastasis and poor prognosis in patients with breast cancer. These data define a previously unappreciated role for pathogenic antibodies derived from tumor-educated B cells in establishing the lymph node premetastatic niche and promoting breast cancer metastasis.

Gu Y, Liu Y, Fu L, Zhai L, Zhu J, Han Y, et al. Tumor-educated B cells selectively promote breast cancer lymph node metastasis by HSPA4-targeting IgG. Nat Med 2019;25:312–22.

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