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

描述（申请人提供）：临床证据的积累使得免疫治疗癌症成为一种非常有前景的治疗策略。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导致不支持的肿瘤免疫监视和最终肿瘤促炎症的主导地位。我们的长期目标是发现能够促进抗肿瘤细胞介导的免疫反应的关键炎症信号，并改变肿瘤微环境，使其有利于肿瘤的根除。白细胞介素-33是IL-1细胞因子家族的一员，在创伤或感染时由坏死细胞或活化的先天免疫细胞（如巨噬细胞）释放。因此，IL-33被认为是一种内源性“危险信号”，可触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免疫应答中的作用。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。我们的研究进一步揭示了IL-33受体ST2在CD8肿瘤浸润淋巴细胞（til）和Th1条件下培养的CD8 T细胞中高表达。更有趣的是，我们已经证明T-bet， Th1分化的关键转录因子是ST2表达所必需的

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.