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).
|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|
|Baatar, Dolgor; Olkhanud, Purevdorj B; Wells, Valerie et al. (2009) Tregs utilize beta-galactoside-binding protein to transiently inhibit PI3K/p21ras activity of human CD8+ T cells to block their TCR-mediated ERK activity and proliferation. Brain Behav Immun 23:1028-37|
|Olkhanud, Purevdorj B; Baatar, Dolgor; Bodogai, Monica et al. (2009) Breast cancer lung metastasis requires expression of chemokine receptor CCR4 and regulatory T cells. Cancer Res 69:5996-6004|