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

基本信息

批准号：
8443458
负责人：
Binfeng Lu
金额：
$ 16.58万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-01-03 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8443458
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

项目摘要

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（由申请人提供）：积累的临床证据已经使癌症免疫疗法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性质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会导致肿瘤免疫监视不受支持，并最终导致肿瘤促进炎症占主导地位。我们的长期目标是发现关键的炎症信号，这些信号可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环境。 Interleukin-33 是细胞因子 IL-1 家族的成员，在创伤或感染期间由坏死细胞或激活的先天免疫细胞（例如巨噬细胞）释放。因此，IL-33被认为是一种内源性“危险信号”，可引发炎症并促进细胞介导的免疫反应。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 IL-33 在从对疫苗有反应的肿瘤中分离的巨噬细胞中表达。我们的研究进一步表明，ST2（IL-33 的一种受体）在 CD8 肿瘤浸润淋巴细胞 (TIL) 以及在 Th1 条件下培养的 CD8 T 细胞中高表达。更有趣的是，我们通过以下方法证明了 T-bet（Th1 分化的关键转录因子）是 ST2 表达所必需的 CD8 T 细胞，表明 ST2 是 CD8 T 细胞中 Th1 程序的一个组成部分。重要的是，我们已经证明 IL-33 与 TCR 或 IL-12 协同作用，可以增加人和小鼠 CD8 T 细胞的功能，例如 IFN 的产生。 B16 黑色素瘤细胞中 IL-33 的表达可有效抑制小鼠体内的肿瘤生长，而不影响体外 B16 增殖。此外，IL-33的表达诱导肿瘤微环境的细胞成分发生变化，有利于肿瘤的根除。我们假设肿瘤环境中免疫“危险信号”IL-33 的表达促进了针对癌症的 Tc1 免疫反应。提出以下目标来检验这一假设：具体目标 1. 确定 IL-33 是否在体内通过 CD8 T 细胞抑制肿瘤生长。具体目标 2. 确定 IL-33 在已确定肿瘤的过继性 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作为一种新的候选肿瘤治疗细胞因子脱颖而出，因为它可以直接增强抗肿瘤CD8 T细胞的功能，还可以改变肿瘤微环境以实现更有效的抗肿瘤免疫反应。我们发现“危险信号”细胞因子IL-33可以促进TC1功能，这将为增强CD8 T细胞针对肿瘤细胞的反应提供新的免疫刺激途径。