Cellular and molecular mechanisms underlying IL-33-mediated anti-tumor immunity

IL-33介导的抗肿瘤免疫的细胞和分子机制

• 批准号: 8602513
• 负责人: Binfeng Lu
• 金额: $ 19.4万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-03 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8602513
• 关键词: Adoptive Transfer; Affect; Biological Markers; CD8B1 gene; Cancer Vaccine Related Development; Cell Culture Techniques; Cell physiology; Cells; Clinical; Cytokine Signaling; Environment; Family; Gene-Modified; Goals; Growth; Human; Immune; Immune response; Immunity; Immunologic Monitoring; Immunotherapy; In Vitro; Infection; Inflammation; Inflammatory; Interferons; Interleukin-1; Interleukin-12; Interleukins; Knowledge; Malignant Neoplasms; Mediating; Melanoma Cell; Molecular; Monitor; Mus; Nature; Necrosis; Pathway interactions; Production; Protocols documentation; Role; Signal Transduction; System; T cell response; T cell therapy; T-Cell Depletion; T-Lymphocyte; Testing; Therapeutic; Translations; Transplantation; Trauma; Tumor Immunity; Tumor-Infiltrating Lymphocytes; Vaccination; Vaccines; Work; base; cancer immunotherapy; cell mediated immune response; cytokine; improved; in vivo; insight; macrophage; melanoma; member; neoplastic cell; novel; novel strategies; programs; public health relevance; receptor; research study; response; tumor; tumor eradication; tumor growth; tumor microenvironment

DESCRIPTION (provided by applicant): Accumulating clinical evidence has made immunotherapy of cancer as a very promising therapeutic strategy. However, the highly immune suppressive nature of the tumor microenvironment has been the main challenge for such approach. Within the tumor microenvironment, the lack of proper immune stimulatory signals results in unsupported tumor immunosurveillance and eventual dominance of tumor promoting inflammation. Our long term goal is to discover critical inflammatory signals that can promote anti-tumor cell-mediated immune responses and alter tumor microenvironment to one that favors tumor eradication. Interleukin-33 is a member of the IL-1 family of cytokines and is released by necrotic cells or activated innate immune cells such as macrophages during trauma or infection. Thus, IL-33 is thought to serve as an endogenous "danger signal" to trigger inflammation and promote cell-mediated immune responses. Prior studies have supported the role of IL-33 in promoting Th2 as well as Th1 immune responses. Whether IL-33 is involved in anti-tumor immune response is unclear. We have recently found that IL-33 is expressed in macrophages isolated from tumors responsive to vaccine. Our study has further revealed that ST2, a receptor for IL-33, is highly expressed in CD8 tumor infiltrating lymphocytes (TILs) as well as CD8 T cells cultured in Th1 conditions. More interestingly, we have demonstrated that T-bet, a critical transcriptional factor of the Th1 differentiation is required for ST2 expression by CD8 T cells, suggesting ST2 is an integral part of the Th1 program in CD8 T cells. Importantly, we have demonstrated that IL-33 synergized with TCR or IL-12 in increasing both human and mouse CD8 T cell functions such as IFN production. The expression of IL-33 in B16 melanoma cells potently inhibits tumor growth in mice without affecting B16 proliferation in vitro. Moreover expression of IL-33 induced changes in the cellular components of the tumor microenvironment that favor tumor eradication. We hypothesize that the expression of immunological "danger signal" IL-33 in the tumor environment promotes Tc1 immune responses against cancer. Following aims are proposed to test this hypothesis: Specific Aim 1. To determine whether IL-33 inhibits tumor growth through CD8 T cells in vivo. Specific Aim 2. To determine the role of IL-33 in adoptive T cell therapy of an established tumor. Our study will reveal how IL-33 promotes anti-tumor immune responses, and represents a novel anti-tumor pathway. IL-33 stands out as a new candidate tumor therapeutic cytokine because it can directly enhance the function of anti-tumor CD8 T cells and also alter the tumor microenvironment to allow more effective antitumor immune responses. Our finding that "danger signal" cytokine IL-33 can promote TC1 function will provide a new immune stimulatory pathway for enhancing CD8 T cell responses against tumor cells.

描述(申请人提供)：越来越多的临床证据使免疫治疗癌症成为一种非常有前途的治疗策略。然而，肿瘤微环境的高度免疫抑制特性一直是这种方法的主要挑战。在肿瘤微环境中，缺乏适当的免疫刺激信号导致没有支持的肿瘤免疫监视，并最终主导肿瘤促炎。我们的长期目标是发现关键的炎症信号，以促进抗肿瘤细胞介导的免疫反应，并将肿瘤微环境改变为有利于肿瘤根除的微环境。白介素33是细胞因子IL-1家族的一员，在创伤或感染时由坏死细胞或激活的先天免疫细胞如巨噬细胞释放。因此，IL-33被认为是触发炎症和促进细胞免疫反应的内源性“危险信号”。先前的研究支持IL-33在促进Th2和Th1免疫反应中的作用。IL-33是否参与抗肿瘤免疫反应尚不清楚。我们最近发现，从对疫苗有反应的肿瘤分离的巨噬细胞中有IL-33的表达。我们的研究进一步表明，IL-33的受体ST2在CD8肿瘤浸润性淋巴细胞(TIL)和在Th1条件下培养的CD8T细胞中高表达。更有趣的是，我们已经证明了T-bet是Th1分化的关键转录因子，通过以下方式表达ST2 CD8T细胞，提示ST2是CD8T细胞Th1程序的组成部分。重要的是，我们已经证明了IL-33与TCR或IL-12在增加人和小鼠CD8 T细胞功能(如产生干扰素)方面具有协同作用。IL-33在B16黑色素瘤细胞中的表达在不影响B16体外增殖的情况下有效地抑制了小鼠肿瘤的生长。此外，IL-33的表达导致肿瘤微环境的细胞成分发生变化，有利于肿瘤的根除。我们假设，免疫“危险信号”IL-33在肿瘤环境中的表达促进了Tc1对癌症的免疫反应。具体目的：1.确定IL-33是否通过体内CD8 T细胞抑制肿瘤生长。具体目的2.确定IL-33在肿瘤过继T细胞治疗中的作用。我们的研究将揭示IL-33如何促进抗肿瘤免疫反应，并代表一种新的抗肿瘤途径。IL-33可直接增强抗肿瘤CD8 T细胞的功能，改变肿瘤微环境，使抗肿瘤免疫反应更加有效，是一种新的候选肿瘤治疗细胞因子。我们发现“危险信号”细胞因子IL-33可促进Tc1功能，为增强CD8T细胞对肿瘤细胞的应答提供了一条新的免疫刺激途径。