The origin of tBregs and their trans-differentiation in cancer

National Institute On Aging

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Abstract

We continue our study 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). These cells (termed tBregs) are directly induced by cancer cells producing metabolites of 5-lipoxygenase pathway (5-LOX) via activating the proliferator-activated receptor alpha (PPARa) signaling in B cells (Wejksza et al., J. Immunology, 2013). tBregs express high levels of TGFb and support cancer metastasis utilizing several mechanisms, such as by suppressing activity of effector T cells, inducing the generation of FoxP3+ Tregs, and educating the regulatory function of both the monocyte and granulocyte subpopulations of MDSCs via triggering TgfbR1/TgfbR2 signaling. Although Tregs and MDSCs are the key metastasis-supporting cells, our data place tBregs upstream of these two cells, explain why the loss of tBregs alone almost completely abrogates metastasis (Bodogai et al., Cancer Research, 2015; Olkhanud et al, Cancer Research, 2011). Our data indicate that cancer-induced B cells/B regulatory cells play important roles in metastasis (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). However, we reported that strategies that target "wrong" B cells can instead be harmful. For example, because tBregs express low levels of surface CD20, current FDA-approved antibody that depletes B cells by targeting CD20 (Rituximab/Rituxan) eliminates beneficial B cells but enriches for tBregs and thereby exacerbates metastasis in mice (Bodogai et al., Cancer Research, 2013), explaining a recent failure of this strategy in humans with solid tumors. We also reported that to generate tBregs, cancer uses TSLP to cause premature emigration and peripheral accumulation of B-cell precursors from the bone marrow (BM) pre-B cells (Ragganoud et al, Cancer Research, 2019). Now I report successful completion of very unique and high-risk study, which we initiated a couple years ago. Because B cells in the spleen of mice with cancer upregulated expression of macrophage-specific genes, we hypothesized that cancer coopts differentiation of prematurely emigrated BM B cell precursors into macrophages. Using various murine tumor models and samples from humans with breast and ovarian cancers, we confirm this hypothesis and report that cancer cells indeed coopt differentiation of the extra nodal B-cell precursors to generate macrophages (termed B-MF). However, to do this, cancer targets o a small subset of CSF1R+ Pax5Low cells within BM pre-B and immature B cells emigrated into the circulation. We link this process at least to cancer-secreted M-CSF, which we found is needed to downregulate Pax5 via CSF1R signaling in the B cell precursors. Overall, cancer generates tumor-associated macrophages (TAM) from B-cell precursors besides their primary source, monocytes. Unlike monocyte-derived TAM, we show that B-MF exhibit a superb ability to induce FoxP3+ Tregs, suppress proliferation of T cells and more efficiently phagocytize apoptotic cells. Clinical relevance of our finding is that cancer uses B-MF to mediate cancer escape. The paper reporting our findings has been submitted for publication and is under revision in Nature Communications (a high-impact, peer-reviewed journal).