Regulatory immune cells in immune suppression and metastasis

调节免疫细胞在免疫抑制和转移中的作用

• 批准号: 8335865
• 负责人: Arya Biragyn
• 金额: $ 24.44万
• 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/8335865
• 关键词: Autoimmune Diseases; Autoimmune Responses; Autoimmunity; B-Lymphocytes; Binding Proteins; Biological; Brain; Breast Cancer Cell; CCR6 gene; CD19 gene; CD4 Positive T Lymphocytes; CD8B1 gene; Carcinoma; Cell Count; Cell physiology; Cells; Clinical; Cytotoxic T-Lymphocytes; Data; Disease Outcome; Elderly; Event; Human; Immune; Immune response; Immune system; Immunologic Surveillance; Immunosuppression; Impairment; Inbred BALB C Mice; Incidence; Laboratories; Lectin; Liver; Lung; Maintenance; Malignant Neoplasms; Mammary gland; Mediating; Molecular; Mus; Myelogenous; NK Cell Activation; Natural Killer Cells; Nature; Neoplasm Metastasis; Patients; Process; Publishing; Regulation; Regulatory T-Lymphocyte; Rest; Role; Signal Transduction; Staging; Study models; T-Lymphocyte; Testing; Vaccines; Work; age related; anticancer research; beta-galactoside; bone; cancer cell; cancer initiation; cell type; combat; immune function; implantation; improved; killings; malignant breast neoplasm; neoplastic cell; peripheral blood; peripheral tolerance; prevent; response; tumor

We have found that breast cancer lung metastasis is actively facilitated by Tregs, as in their absence, the inherent capability of tumors alone to migrate into inflamed lungs was not sufficient to establish lung metastasis (Olkhanud et al., 2009). Lung metastasis required an active participation of CCR4+ Tregs. The biological role of Tregs was to infiltrate lungs together with tumor cells to regulate or even kill anti-tumor NK cells. This presumably explains our finding that NK cell counts were significantly reduced in peripheral blood (PB) of both tumor-bearing mice and human patients with an advanced stage IV breast cancer. Thus, strategies that abrogate any part of this process, such as targeted inactivation of CCR4+ cells or direct depletion of Tregs, would be expected to improve the outcome of the disease. This in turn would activate both antitumor innate and adaptive immune responses through activation of NK cells and cytolytic T cells. Interestingly, the Tregs killed NK cells by utilizing beta-galactoside-binding protein (bGBP), the same lectin-type factor shown by our group to regulate the maintenance and control of peripheral tolerance by inducing non-cytotoxic TCR signaling of CD8+ T cells (Baatar et al., 2009). Despite this, Tregs may not to be a sole cell type that promotes lung metastasis. We have recently found that breast cancer cells control the Treg expansion utilizing previously unknown regulatory immune cell-mediated mechanism. To do this, 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 tumor-evoked Bregs (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. This work was recently published in Cancer Research (Olkhanud et al., 2011). The clinical implications of our findings are that, to effectively combat cancer and cancer metastasis, tBregs have to be controlled to interrupt the initiation of cancer-induced suppressive events. In addition, considering the assumption that cancer usually hijacks the existing machinery of immune regulation, 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.

我们已经发现，Tregs积极促进乳腺癌的肺转移，因为在没有Tregs的情况下，肿瘤本身迁移到发炎肺的固有能力不足以确定肺转移(Olkhanud等人，2009年)。肺转移需要CCR4+Tregs的积极参与。Tregs的生物学作用是与肿瘤细胞一起侵入肺部，调节甚至杀伤抗肿瘤的NK细胞。这可能解释了我们发现荷瘤小鼠和晚期乳腺癌患者外周血(PB)中的NK细胞数量显著减少的原因。因此，消除这一过程的任何部分的策略，如靶向灭活CCR4+细胞或直接耗尽Tregs，有望改善疾病的结局。这反过来将通过激活NK细胞和细胞溶解T细胞来激活抗肿瘤先天免疫反应和获得性免疫反应。有趣的是， Tregs通过利用β-半乳糖苷结合蛋白(BGBP)杀死NK细胞，该蛋白与我们小组展示的凝集素类型因子相同，通过诱导CD8+T细胞的非细胞毒性TCR信号来调节外周耐受的维持和控制(Batal等人，2009年)。 尽管如此，Tregs可能不是唯一促进肺转移的细胞类型。我们最近发现，乳腺癌细胞利用先前未知的免疫细胞调节机制控制Treg的扩张。为此，癌细胞首先以B细胞为靶点，促使正常B细胞转化为低增殖调节性CD19+CCR6+CD25High B7-H1 High CD86 High CD62LowIgMInt/Low细胞，表达构成活性的STAT3。这些细胞的主要功能被称为肿瘤诱发T细胞(TBregs)，其主要功能是诱导静止的CD4+T细胞转化成FoxP3+Tregs。事实上，我们的数据可以被认为是癌症相关Bregs的第一个证据。这项工作最近发表在《癌症研究》(Olkhanud等人，2011年)上。我们的发现的临床意义是，为了有效地对抗癌症和癌症转移，tBregs必须得到控制，以阻断癌症诱导的抑制事件的启动。此外，考虑到癌症通常会劫持现有的免疫调节机制的假设，tBregs可能是正常免疫功能的一部分，阻止诱导自身免疫反应。因此，它们的损害可能解释了与年龄相关的自身免疫性疾病的发生率和老年人对疫苗反应差的原因。我的实验室正在进行的研究的初步结果支持这一假设。