Here we continue our studies of regulatory B cells, which we discovered in some mice and humans with cancer (Olkhanud et al, Cancer Research, 2011; Bodogai et al. Cancer Research, 2013). Cancer cells produce metabolites of 5-lipoxygenase pathway (5-LOX), which then activate the proliferator-activated receptor alpha (PPARa) signaling in B cells and convert them into regulatory B cells, which we termed tBregs (Wejksza et al., J. Immunology, 2013). Although tBregs can suppress activity of effector T cells, they primarily supported cancer metastasis by inducing the generation of FoxP3+ Tregs or/and educating MDSCs. Both processes involved TGF. As others reported, cancer markedly expands MDSCs. However, we found that they only have a partially primed suppressive activity that is not sufficient to support metastasis. tBregs empower MDSCs with a full regulatory and pro-metastatic functions. We show that tBregs directly activate the regulatory function of both the monocyte and granulocyte subpopulations of MDSC by relying in part on TgfbR1/TgfbR2 signaling. MDSC fully educated in this manner exhibit an increased production of ROS and NO and more efficiently suppress CD4+ and CD8+ T cells, thereby promoting tumor growth and metastasis. Thus, loss of tBregs or Tgfbr deficiency in MDSC is sufficient to disable their suppressive function and to block metastasis. Overall, our data indicate that cancer-induced B cells/B regulatory cells are important regulators of the immune suppressive and pro-metastatic functions of MDSC (Bodogai et al., Cancer Research, 2015), suggesting that strategies that inactivate tBregs can improve antitumor immune responses (Lee-Chang et al., J. Immunol., 2013; Bodogai et al., Cancer Research, 2013). Because tBregs express low levels of CD20, we propose that the use of CD20-targeting antibody rituximab may not benefit or even can be harmful in cancer patients containing tBregs. The rituximab treatment enriched for tBregs and thereby exacerbated metastasis in mice, explaining a recent failure of this strategy in humans with solid tumors. The source of B cells that become tBregs remained unknown. Here, we report that they are early B-cell progenitors from the bone marrow (BM), such as pre-B cells. Although these cells reside in BM, cancer cancer promotes their premature emigration from BM and expansion in the circulation. Mechanistically, to this, cancer produces thymic stromal lymphopoietin (TSLP), which we show promotes premature emigration of B-cell progenitors from the BM by downregulating their CXCR4 and VLA4 expression. TSLP is also necessary for the expansion and subsequent conversion of CD25+ pre-B-like cells. Similar process appears to occur in humans with breast cancer. Overall, our study revealed previously unknown pathway that cancer utilizes to generate metastasis-promoting regulatory B cells. Moreover, it also suggested that the TSLP/TSLPR axis can be a therapeutic target to control cancer metastasis, because the loss of TSLP expression in cancer cells or TSLPR deficiency in B cells impairs lung metastasis of 4T1 cancer cells. This finding has been submitted for publication (Ragganoud et al, 2019).
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