We have made significant progress in the field by demonstrating the importance of regulatory immune cells in metastasis. For example, using mice with metastatic 4T1 cancer we found that regulatory T cells (Tregs) are required for the success of lung metastasis. In their absence, the inherent capability of cancer cells to migrate into inflamed lungs was not sufficient to establish lung metastasis. The mechanism of this process was that CCR4+ Tregs co-migrated with CCR4+ cancer cells into the lungs to kill antitumor NK cells using beta-galactoside-binding protein (bGBP)(Olkhanud et al., 2009). Despite this, Tregs require participation of additional regulatory immune cells. We have recently found that cancer controls the Treg expansion utilizing previously unknown regulatory immune cell-mediated mechanism. Cancer cells first targeted B cells to evoke the conversion of normal B cells into a poorly proliferative regulatory CD19+ CCR6+ CD25High B7-H1 High CD86 High CD62LowIgMInt/Low cells that express constitutively-active Stat3. The primary function of these cells, designated tBregs, was to induce conversion of FoxP3+ Tregs from resting CD4+ T cells. In fact, our data can be considered as the first proof of cancer-associated Bregs (Olkhanud et al., 2011a). Interestingly, although CCR4+ Th2-type CD4+ T cells can have suppressive functions and be recruited into the inflamed lungs, we found that they mostly control progression of primary cancer in the mammary gland but not metastasis. The mechanism of this process was that primary cancer had to express TSLP to polarize CD4+ T cells utilizing TSLPR (Olkhanud et al., 2011b). The clinical implications of our findings are that, to effectively combat cancer escape and metastasis, the inactivation of the any part of this process, such as Tregs or tBregs, can block cancer escape. Here, we report a new finding that tBreg-generation requires the proliferator-activated receptor alpha (PPARa) signaling. The mechanism of this process is that breast 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. The manuscript describing these findings has been recently submitted for publication (Wejksza et al., 2012). We also found human tBregs in peripheral blood of patients with B-CLL, thus definitively confirming our earlier hypothesis on their existence in humans. Unlike conventional B cells, murine and human tBregs express low levels of CD20. These results also explain recent failure of anti-CD20 Ab/rituximab to benefit humans with solid tumors questions the importance of therapeutic inactivation of B cells to combat cancer escape. Anti-CD20 Ab mostly enriches for tBregs by depleting good B cells both in tumor-bearing mice and patients with B-CLL. In modeling studies using mice with established 4T1.2 breast cancer, we show that this enrichment of tBregs results in a significant enhancement of cancer progression and lung metastasis. In contrast, cancer escape can be effectively blocked by inactivation of tBregs with stimulatory CpG oligonucleotides delivered with CXCL13. Unlike most toll-like receptor (TLR) ligands, CpG inhibits the inhibitory activity of tBregs and makes them stimulatory for T cells by up regulating expression of 4-1BBL. Thus, we elucidated the mechanism of action of tBregs, a method for their inhibition that changes their phenotype to immune stimulation, and explained the failure of immunomodulation with anti-CD20 to induce immune-mediated cancer cell killing in vivo. This study has been submitted for publication (Bodogai et al., 2012). In addition, by assuming that cancer usually hijacks the existing machinery of immune regulation, we hypothesize that tBregs may be a part of normal immune function that prevents the induction of autoimmune responses. As such, their impairment may explain the age-related incidences of autoimmune diseases and poor vaccine responses in elderly. The preliminary results from ongoing studies in my laboratory support this hypothesis. We also actively collaborated with CRB and Dr. Goetzl to understand immunoregulatory role of adenosine in old humans (Hesdorffer et al., 2012).

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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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