Tumor-Derived Thymic Stromal Lymphopoietin Expands Bone Marrow B-cell Precursors in Circulation to Support Metastasis

Immature B cells in the bone marrow emigrate into the spleen during adult lymphopoiesis. Here, we report that emigration is shifted to earlier B-cell stages in mice with orthotopic breast cancer, spontaneous ovarian cancer, and possibly in human breast carcinoma. Using mouse and human bone marrow aspirates and mouse models challenged with highly metastatic 4T1 breast cancer cells, we demonstrated that this was the result of secretion of thymic stromal lymphopoietin (TSLP) by cancer cells. First, TSLP downregulated surface expression of bone marrow (BM) retention receptors CXCR4 and VLA4 in B-cell precursors, increasing their motility and, presumably, emigration. Then, TSLP supported peripheral survival and proliferation of BM B-cell precursors such as pre-B–like cells. 4T1 cancer cells used the increased pool of circulating pre-B–like cells to generate metastasis-supporting regulatory B cells. As such, the loss of TSLP expression in cancer cells alone or TSLPR deficiency in B cells blocked both accumulation of pre-B–like cells in circulation and cancer metastasis, implying that the pre-B cell–TSLP axis can be an attractive therapeutic target. Significance: Cancer cells induce premature emigration of B-cell precursors from the bone marrow to generate regulatory B cells. CD19+ B cells were FACS sorted from spleens of control naive or 4T1 cancer-bearing mice (female, BALB/c mice, N=3 per experimental group). CD19+ B cells of tumor-baring mice were further sorted into CD23+ (follicular B cells) or CD23-, CD25- (pro-B cell) or CD23-, CD25+ (pre-B cell) populations. CD19+ B cells from naïve mice were in vitro stimulated with 4T1 or 4T1-PE cancer cell conditioned media for 2 days, as described in Olkhanud et al., Cancer Research, 2011, to generate TU4T1 and TU4T1_PE cells, respectively. In addition, CD19+ B cells from naïve mice were in vitro stimulated with BAFF/Blys or with 4T1-P