Role of Stat3 in Tumor Immune Evasion and Immune Suppression

描述（由申请人提供）：肿瘤免疫学中的一个长期存在的问题，对癌症免疫治疗构成了严重的挑战，这就是为什么肿瘤杀伤性CD 8 + T细胞不能有效地浸润肿瘤。与此形成鲜明对比的是，诱导免疫抑制并促进肿瘤生长和转移的CD 4 + T细胞，特别是调节性T细胞，在肿瘤中积聚。我们实验室和其他小组的广泛研究表明，STAT 3是一种对肿瘤细胞存活和侵袭至关重要的信号转导和转录激活因子家族蛋白，介导肿瘤细胞与各种免疫细胞之间的串扰，导致肿瘤免疫抑制。在过去的五年中，我们的工作进一步确立了STAT 3在影响荷瘤宿主中CD 8+和CD 4 + T细胞方面的作用。我们的研究结果表明，CD 4 + T细胞内的STAT 3活性对其肿瘤积聚至关重要。相比之下，CD 8 + T细胞固有的STAT 3抑制其肿瘤浸润。基于这些发现，我们假设CD 4+和CD 8 + T细胞的肿瘤募集利用不同的信号通路/因子，导致相反的生物学功能，从而促进肿瘤进展。在本申请中，我们将通过检查鞘氨醇-1-磷酸（S1 P）及其受体S1 PR 1的信号传导（我们已经证明其对肿瘤细胞和肿瘤相关免疫细胞中持续的STAT 3激活至关重要）是否对CD 4 + T细胞动员到肿瘤部位至关重要来验证我们的假设。我们还将评估STAT 3抑制诱导的干扰素（IFN）和T细胞引诱剂（也称为趋化因子）表达是否会导致CD 8 + T细胞肿瘤浸润。此外，我们建议解剖出详细的分子机制，S1 P/S1 PR 1-STAT 3信号和STAT 3抑制诱导的IFN/趋化因子信号调节CD 4+和CD 8 + T细胞动员到肿瘤部位，分别。我们提出的研究结果可能会产生关于荷瘤宿主中CD 8+和CD 4 + T细胞不平衡的基本机制的新知识，并确定新的靶点，以潜在地开发范式转移癌症免疫方法。

DESCRIPTION (provided by applicant): A long-standing problem in tumor immunology that poses a serious challenge for cancer immunotherapy is why tumor-killing CD8+ T cells do not efficiently infiltrate tumors. In stark contrast, CD4+ T cells, especially regulatory T cells, which induce immunosuppression and promote tumor growth and metastasis, accumulate in tumors. Extensive studies from our laboratory and other groups show that STAT3, a Signal Transducer and Activator of Transcription family protein critical for tumor cell survival and invasion, mediates the crosstalk between tumor cells and various immune cells, causing tumor immunosuppression. Over the last five years, our work further establishes a role of STAT3 in impacting both CD8+ and CD4+ T cells in tumor-bearing hosts. Our results suggest that STAT3 activity within CD4+ T cells is critical for their tumor accumulation. By contrast, STAT3 intrinsic to CD8+ T cells inhibits their tumor infiltration. Based on these findings, we hypothesize that tumor recruitment of CD4+ and CD8+ T cells utilizes distinct signaling pathways/factors, resulting in opposing biological functions that enhance tumor progression. In this application, we will test our hypothesis by examining whether signaling of sphingosine-1-phosphate (S1P) and its receptor, S1PR1, which we have demonstrated to be critical for persistent STAT3 activation in tumor cells and tumor-associated immune cells, is essential for CD4+ T cell mobilization to tumor sites. We will also assess whether STAT3 inhibition-induced expression of interferon (IFN) and T cell attractants, also known as chemokines, causes CD8+ T cell tumor infiltration. Moreover, we propose to dissect out detailed molecular mechanisms by which S1P/S1PR1-STAT3 signaling and STAT3 inhibition-induced IFN/chemokine signaling modulate CD4+ and CD8+ T cell mobilization to tumor sites, respectively. Results from our proposed studies will likely generate new knowledge on fundamental mechanisms underlying the imbalance of CD8+ and CD4+ T cells in tumor-bearing hosts, as well as identify new targets to potentially develop paradigm-shifting cancer immunotherapeutic approaches.