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. 1. Recently, we also reported that to generate tBregs, cancer expresses TSLP that causes premature emigration and peripheral accumulation of B-cell precursors from the bone marrow (BM) pre-B cells (Ragganoud et al, Cancer Research, 2019). During this study we found that cancer-activated B cells up regulate expression of macrophage-specific genes, raising an interesting possibility that cancer also causes transdifferentiation of B cells into tumor-associated macrophages. We recently reported that some cancers induce accumulation of bone marrow (BM) B-cell precursors in the spleen to convert them into metastasis-promoting, immunosuppressive B cells. Here, using various murine tumor models and samples from humans with breast and ovarian cancers, I report that cancer cells indeed coopt differentiation of the extra nodal B-cell precursors to generate macrophages (termed B-MF). We link the trans-differentiation to a small subset of CSF1R+ Pax5Low cells within BM pre-B and immature B cells and cancer-secreted M-CSF that downregulates Pax5 via CSF1R signaling. Thus, cancer generates tumor-associated macrophages (TAM) from B-cell precursors besides their primary source, monocytes. Based on their differences from monocyte-derived TAM, such as a superb ability to induce FoxP3+ Tregs, suppress proliferation of T cells and more efficiently phagocytize apoptotic cells, we propose that cancer generates B-MF to mediate cancer escape. The 1st part of this study is completed and submitted for publication (Chen et al., Submitted, 2021). 2. Our recent results suggest that B cells may also affect cancer in aged hosts. We found that depending on a cancer type, cancer progression is either increased or decreased in aging. This differential response we now link to aging-dysregulated B cells. Unfortunately, the COVID-19 quarantine temporarily hampered the progress of this novel and exciting study. Several essential strains of mice we were breeding for this study were lost due to the COVI-19 rules of our animal facility. We therefore expect to complete this study and submit paper for publication sometime late 2022.