In 2011, we have reported (Olkhanud et al, Cancer Research, 2011) that breast cancer uses previously unknown type of regulatory cells, termed tBregs. tBregs protected metastasizing cancer cells from the attack by immune cells by inducing the generation of Tregs. We also reported (Wejksza et al., J. Immunology, 2013) that cancer cells induce tBregs from resting B cells by producing metabolites of 5-lipoxygenase pathway (5-LOX) to target the proliferator-activated receptor alpha (PPARa) signaling. However, it was difficult mechanistically to understand how 5-LOX metabolites, so-called eicosanoids, are delivered to B cells. Here, we report that cancer uses small extracellular vesicles, exosomes, to deliver eicosanoids to B cells. This is very interesting result with significant clinical relevance. The finding is being prepared for report as a manuscript. In 2013 we reported (Bodogai et al. Cancer Research, 2013) that some subsets of human B-CLL are derived from tBregs, thus further reinforcing our original hypothesis that tBregs also exist in humans with cancer. We also demonstrated that tBregs are important suppressers of antitumor CD8+T cells and the inactivation of tBregs inversely associates with the expansion of antitumor CD8+T cells. Although we have devised a number of strategies that inactivate tBregs to improve antitumor immune responses (Lee-Chang et al., J. Immunol., 2013), depletion of B cells with a current clinical approach such as the use of CD20-targeting antibody rituximab can instead be harmful. Rituximab augments cancer escape and metastasis via enriching tBregs that express low levels of CD20. Although it is widely accepted that MDSCs primarily control cancer escape, we noticed that cancer fails to metastasize if B cells or tBregs are lost despite unaltered expansion of MDSCs. Here we report that tBregs play a very important role in activation of cancer-expanded MDSCs. We found that MDSC populations have only partially primed regulatory function and limited pro-metastatic activity unless they are fully educated by tBregs. Cancer-induced tBregs directly activate the regulatory function of both the monocyte and granulocyte subpopulations of MDSC, relying in part on TgfβR1/TgfβR2 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 TgfβR 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. This finding has been recently reported (Bodogai et al., Cancer Research, 2015). Overall, during the reported period we have made a number of novel findings: (i) Cancer cells use exosomes to communicate and control function of B cells; and (ii) Cancer uses B cells and tBregs to educate MDSCs rendering them fully suppressive and pro-metastatic. These results have significant clinical and immunological importance. A rising interest in our study resulted in publication of two invited book chapters Biragyn et al. (Regulatory B cells, Method in Mol. Biol., Humana press, 2014) and Biragyn et al. (N cells in anti-tumor immunity, Encyclopedia of Immunology, Elsevier, 2015) and one collaborative research papers (Kapogiannis et al., FASEB J, 2015) .
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