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: 8931545
• 负责人: Arya Biragyn
• 金额: $ 48.51万
• 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/8931545
• 关键词: Antibodies; Ants; Arachidonate 5-Lipoxygenase; Autoimmune Diseases; B-Lymphocytes; Biological; Book Chapters; CCR6 gene; CD19 gene; CD8B1 gene; Cell physiology; Cells; Clinical; Conditioned Culture Media; Failure; Generations; Genetic; Goals; Human; Immune; Immune response; Immunoglobulin M; Immunology; Immunosuppression; Impairment; Leukotriene B4; Lung; Lymphoid; MS4A1 gene; Malignant Neoplasms; Mediating; Metabolic; Mus; Myelogenous; Neoplasm Metastasis; Pathway interactions; Play; Publications; Regulation; Regulatory T-Lymphocyte; Reporting; Role; Signal Transduction; Solid Neoplasm; Study models; T-Lymphocyte; anticancer research; cancer cell; clinically relevant; fatty acid oxidation; interest; malignant breast neoplasm; novel marker; prevent; programs; receptor; response; rituximab; tumor

In 2013 we reported (Bodogai et al. Cancer Research, 2013) new markers that can be used for characterization of tBregs, such as 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. Importantly, clinical relevance of tBregs expressing low levels of 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.Our results (Olkhanud et al, Cancer Research, 2009; 2011; Bodogai et al. Cancer Research, 2013) indicate the importance of tBregs and concurrently Tregs in regulation of anticancer responses to facilitate cancer escape and metastasis. In contrast, others reported that cancer expands MDSC to metastasize. Here we report that MDSCs fail to support metastasis if B cells are deficient, as their regulatory activity is impaired in the absence of tBregs. We found that cancer targets B cells, such as tumor-evoked regulatory B cells (tBregs) to render MDSCs regulatory. Utilizing TGFb-Tgfr1/Tgfr2 axis tBregs increase suppressive and thereby pro-metastatic activity of tumor-expanded PMN- and Mo-MDSCs. Thus, the cancer-induced expansion of MDSCs per se is not criteria of their regulatory state; the regulatory activity of MDSCs requires an additional activation pathway, tBregs/B cells. We recently reported (Wejksza et al., J. Immunology, 2013) that cancer cells target the proliferator-activated receptor alpha (PPARa) signaling to induce the generation of tBregs via metabolites of the 5-lipoxygenase (5-LO) pathway. 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. Here, we report that cancer uses exosomes to deliver 5-LO metabolites to B cells. Cancer exosomes converted tBregs as efficiently as cancer conditioned media. This is very interesting result with significant clinical relevance. A rising interest in our study resulted in publication of two invited book chapters (Lee-Chang, C., et al., he Tumor ImmunoEnvironment. Springer, 2013; and Biragyn et al. Regulatory B cells, Humana press, 2014).

2013年，我们报道了（Bodogai et al. Cancer Research，2013）可用于表征tBBL的新标志物，例如除了CD 19 + CCR 6 + CD 25高CD 81高B7-H1高CD 86高CD 62低IgM Int/Low外，它们还可通过CD 20和4-1BBL的低表达来定义。 重要的是，在tB细胞上表达低水平4-1BBL的tB细胞的临床相关性是防止效应抗肿瘤CD 8 T细胞的活化。利用CD 20-low作为tBCLL的标志物，我们还发现一些人B-CLL可以从tBCLL衍生。因此，这些结果进一步加强了我们最初的假设，即tBcR也存在于癌症患者中。我们的建模研究表明，tBcR的CD 20-低状态保护它们免受利妥昔单抗/抗CD 20抗体的消耗。在患有乳腺癌的小鼠中，抗CD 20 Ab治疗反而是有害的，并且通过富集tBl增加癌症逃逸和转移。我们的结果（Olkhanud et al，Cancer Research，2009; 2011; Bodogai et al. Cancer Research，2013）表明了tBcR和同时TcR在调节抗癌反应以促进癌症逃逸和转移中的重要性。相反，其他人报道癌症使MDSC扩展至转移。在这里，我们报告说，MDSC不能支持转移，如果B细胞是缺乏的，因为它们的调节活性受损，在缺乏tBctin。我们发现，癌症靶向B细胞，如肿瘤诱发的调节性B细胞（tB细胞），使MDSC的调节。利用TGFb-Tgfr 1/Tgfr 2轴，tBcR增加肿瘤扩增的PMN-和Mo-MDSC的抑制活性，从而增加促转移活性。因此，癌症诱导的MDSC扩增本身并不是其调节状态的标准; MDSC的调节活性需要额外的活化途径，即tB细胞/B细胞。 我们最近报道（Wejksza et al.，J. Immunology，2013），癌细胞靶向增殖物激活受体α（PPARa）信号传导以经由5-脂氧合酶（5-LO）途径的代谢物诱导tBcR的产生。B细胞中LTB 4信号传导的失活或PPARa的遗传缺陷阻断了tBB的产生，从而消除了已建立乳腺癌的小鼠的肺转移。因此，除了引发脂肪酸氧化和代谢信号外，PPARa还启动tBl分化所需的程序。我们提出，PPARa在B细胞或/和肿瘤5-LO途径的药理学控制tBreg介导的癌症逃逸的新目标。在这里，我们报告说，癌症使用外来体提供5-LO代谢物的B细胞。癌症外泌体与癌症条件培养基一样有效地转化tBB。这是一个非常有趣的结果，具有显著的临床意义。 对我们研究的兴趣越来越大，导致出版了两本邀请书的章节（Lee-Chang，C.，例如，肿瘤免疫环境。Springer，2013;和Biragyn等人，Regulatory B cells，Humana press，2014）。