We have made significant progress in our study and successfully accomplished the goal for the reported year. We further characterized tBregs we recently discovered and found that, besides CD19+ CCR6+ CD25High CD81High B7-H1 High CD86 High CD62Low IgM Int/Low, they can also be defined by low expression of CD20 and 4-1BBL. Functionally, the low expression 4-1BBL on tBregs is to prevent activation of effector antitumor CD8 T cells. Utilizing CD20-low as a marker of tBregs, we also found that some human B-CLL can be derived from tBregs. Thus, these results further reinforce our original hypothesis that tBregs also exist in humans with cancer. Our modeling studies indicate that the CD20-Low status of tBregs protects them from depletion with rituximab/ant-CD20 antibody. In mice with breast cancer, anti-CD20 Ab treatment is instead harmful and augments cancer escape and metastasis via enriching tBregs. These results also provide a mechanistic explanation of a recent failure of rituximab treatment in humans with solid tumors. The study was recently published (Bodogai et al. Cancer Research, 2013). Although cancer induces tBregs, the mechanism of this process remains unknown. Here we report that they target the proliferator-activated receptor alpha (PPARa) signaling in tBregs. Cancer cells produce metabolites of the 5-lipoxygenase (5-LO) pathway, such as leukotriene B4, to activate PPARa in B cells. Inactivation of LTB4 signaling or genetic deficiency of PPARa in B cells blocks the generation of tBregs and thereby abrogates lung metastasis in mice with established breast cancer. Thus, in addition to eliciting fatty acid oxidation and metabolic signals, PPARa initiates programs required for differentiation of tBregs. We propose that PPARa in B cells or/and tumor 5-LO pathways represents new targets for pharmacological control of tBreg mediated cancer escape. These results we recently publication (Wejksza et al., J. Immunology, 2013). As a result of our success in the field, we have been invited to write several review and opinion articles (Biragyn &Longo, 2012;Biragyn &Lee Chang, 2012). We also successfully conducted collaborative studies with others, such as professor Ed Goetzl (Hesdorffer et al., 2012).

National Institute of Health (NIH)
National Institute on Aging (NIA)
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Freeman, David W; Noren Hooten, Nicole; Eitan, Erez et al. (2018) Altered Extracellular Vesicle Concentration, Cargo, and Function in Diabetes. Diabetes 67:2377-2388
Eitan, Erez; Green, Jamal; Bodogai, Monica et al. (2017) Age-Related Changes in Plasma Extracellular Vesicle Characteristics and Internalization by Leukocytes. Sci Rep 7:1342
Lu, Daoyuan; Cai, Huan; Park, Sung-Soo et al. (2017) Correction for Lu et al., ""Nuclear GIT2 Is an ATM Substrate and Promotes DNA Repair"". Mol Cell Biol 37:
Biragyn, Arya; Aliseychik, Maria; Rogaev, Evgeny (2017) Potential importance of B cells in aging and aging-associated neurodegenerative diseases. Semin Immunopathol 39:283-294
Bodogai, Monica; Moritoh, Kanako; Lee-Chang, Catalina et al. (2015) Immunosuppressive and Prometastatic Functions of Myeloid-Derived Suppressive Cells Rely upon Education from Tumor-Associated B Cells. Cancer Res 75:3456-65
Biragyn, Arya; Lee-Chang, Catalina; Bodogai, Monica (2014) Generation and identification of tumor-evoked regulatory B cells. Methods Mol Biol 1190:271-89
Bodogai, Monica; Lee Chang, Catalina; Wejksza, Katarzyna et al. (2013) Anti-CD20 antibody promotes cancer escape via enrichment of tumor-evoked regulatory B cells expressing low levels of CD20 and CD137L. Cancer Res 73:2127-38
Wejksza, Katarzyna; Lee-Chang, Catalina; Bodogai, Monica et al. (2013) Cancer-produced metabolites of 5-lipoxygenase induce tumor-evoked regulatory B cells via peroxisome proliferator-activated receptor ?. J Immunol 190:2575-84
Biragyn, Arya; Lee-Chang, Catalina (2012) A new paradigm for an old story: the role of regulatory B cells in cancer. Front Immunol 3:206
Biragyn, Arya; Longo, Dan L (2012) Neoplastic ""Black Ops"": cancer's subversive tactics in overcoming host defenses. Semin Cancer Biol 22:50-9

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