Role of Stat3 in Tumor Immune Evasion and Immune Suppression

描述(申请人提供)：肿瘤免疫学中一个长期存在的问题，对癌症免疫治疗构成了严重的挑战，这就是为什么杀伤肿瘤的CD8+T细胞不能有效地渗透到肿瘤中。与之形成鲜明对比的是，CD4+T细胞，尤其是调节性T细胞，诱导免疫抑制，促进肿瘤生长和转移，在肿瘤中积聚。我们实验室和其他研究小组的广泛研究表明，STAT3是一种信号转导和转录激活蛋白家族蛋白，对肿瘤细胞的生存和侵袭至关重要，它介导了肿瘤细胞和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STAT3在影响荷瘤宿主中CD8+和CD4+T细胞方面的作用。我们的结果表明，CD4+T细胞内的STAT3活性对其肿瘤聚集至关重要。相反，CD8+T细胞固有的STAT3抑制其肿瘤侵袭。基于这些发现，我们假设肿瘤对CD4+和CD8+T细胞的募集利用了不同的信号通路/因子，导致了促进肿瘤进展的相反的生物学功能。在这一应用中，我们将通过检测鞘氨醇-1-磷酸(S1P)及其受体S1PR1的信号是否对肿瘤细胞和肿瘤相关免疫细胞中持续的STAT3激活至关重要，来检验我们的假设是否对CD4+T细胞动员到肿瘤部位是必要的。我们还将评估STAT3抑制诱导干扰素和T细胞诱导剂(也称为趋化因子)的表达是否会导致CD8+T细胞肿瘤的侵袭。此外，我们建议剖析S1P/S1PR1-STAT3信号和STAT3抑制诱导的干扰素/趋化因子信号分别调节CD4+和CD8+T细胞向肿瘤部位动员的详细分子机制。我们提出的研究结果可能会对荷瘤宿主CD8+和CD4+T细胞失衡的基本机制产生新的认识，并确定新的靶点，潜在地开发改变范式的癌症免疫治疗方法。

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.