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

描述（由申请人提供）：积累的临床证据使癌症免疫治疗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导致不支持的肿瘤免疫监视和最终的肿瘤促进炎症的主导地位。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，并改变肿瘤微环境，使其有利于肿瘤根除。白细胞介素-33是细胞因子的IL-1家族的成员，并且在创伤或感染期间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的“危险信号”，以触发炎症和促进细胞介导的免疫反应。先前的研究已经支持IL-33在促进Th 2以及Th 1免疫应答中的作用。IL-33是否参与抗肿瘤免疫应答尚不清楚。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的受体ST 2在CD 8肿瘤浸润淋巴细胞（TIL）以及在Th 1条件下培养的CD 8 T细胞中高度表达。更有趣的是，我们已经证明，T-bet，一个Th 1分化的关键转录因子，是ST 2表达所必需的， 表明ST 2是CD 8 T细胞中Th 1程序的组成部分。重要的是，我们已经证明IL-33与TCR或IL-12协同增加人和小鼠CD 8 T细胞功能，如IFN产生。IL-33在B16黑色素瘤细胞中的表达有效地抑制小鼠中的肿瘤生长，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组分的变化，这有利于肿瘤根除。我们推测，免疫学“危险信号”IL-33在肿瘤环境中的表达促进了Tc 1对癌症的免疫应答。以下目标被提出来测试这个假设：具体目标1。确定IL-33是否通过体内CD 8 T细胞抑制肿瘤生长。具体目标2。确定IL-33在已建立肿瘤的过继性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应答，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CD 8 T细胞的功能，并改变肿瘤微环境，以实现更有效的抗肿瘤免疫应答。我们发现“危险信号”细胞因子IL-33可以促进TC 1功能，这将为增强CD 8 T细胞对肿瘤细胞的反应提供新的免疫刺激途径。

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.