Regulatory immune cells in immune suppression: The role of tBregs

调节性免疫细胞在免疫抑制中的作用：tBregs 的作用

• 批准号: 8736566
• 负责人: Arya Biragyn
• 金额: $ 17.13万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8736566
• 关键词: Antibodies; Ants; Arachidonate 5-Lipoxygenase; Autoimmune Diseases; B-Lymphocytes; Biological; CCR6 gene; CD19 gene; CD8B1 gene; Cells; Clinical; Exhibits; Failure; Generations; Genetic; Goals; Human; Immune; Immunoglobulin M; Immunology; Immunosuppression; Leukotriene B4; Lung; MS4A1 gene; Malignant Neoplasms; Mediating; Metabolic; Molecular; Mus; Myelogenous; Neoplasm Metastasis; Pathway interactions; Process; Publications; Publishing; Regulatory T-Lymphocyte; Reporting; Role; Signal Transduction; Solid Neoplasm; Study models; T-Lymphocyte; Writing; anticancer research; cancer cell; clinically relevant; fatty acid oxidation; malignant breast neoplasm; prevent; professor; programs; receptor; response; rituximab; success; tumor

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).

我们的研究取得了重大进展，圆满完成了报告年度的目标。我们进一步表征了我们最近发现的tregs，发现除了CD19+ CCR6+ CD25High CD81High B7-H1 High CD86 High CD62Low IgM Int/Low外，它们还可以通过CD20和4-1BBL的低表达来定义。在功能上，4-1BBL在tregs上的低表达是为了阻止效应抗肿瘤CD8 T细胞的活化。利用CD20-low作为tBregs的标记，我们还发现一些人B-CLL可以来源于tBregs。因此，这些结果进一步强化了我们最初的假设，即tregs也存在于癌症患者中。我们的模型研究表明，tBregs的cd20低状态可以保护它们免受利妥昔单抗/抗cd20抗体的消耗。在患有乳腺癌的小鼠中，抗cd20 Ab治疗反而是有害的，并且通过富集tregs来增加癌症的逃逸和转移。这些结果也为最近利妥昔单抗治疗实体瘤失败提供了机制解释。这项研究最近发表（Bodogai et al.）。癌症研究，2013)。