Myeloid Suppressor Cell-Mediated Immune Suppression of Tumor Specific T Cells

描述(由申请人提供)：越来越多的证据表明，具有抑制表型的宿主免疫细胞对成功的癌症免疫增强治疗构成了重大障碍。在抑制细胞中，T调节细胞(Tregs)和髓系来源的抑制细胞(MDSCs)在晚期恶性肿瘤患者中显著增加。以前，我们发现各种肿瘤的生长导致肿瘤、脾和骨髓中MDSC和Treg的数量显著增加。更有趣的是，我们已经证明，MDSC可以通过诱导T细胞无能和在荷瘤小鼠中发展Treg来介导对肿瘤特异性T细胞反应的抑制。这些结果为MDSC和Treg在荷瘤宿主体内的免疫抑制功能提供了强有力的证据。为了获得持久的抗肿瘤免疫，提高免疫调节治疗的疗效，必须研究和克服肿瘤诱导的免疫抑制。我们的研究表明，通过使用小分子抑制剂(Sunitinib苹果酸；Sutent(R))靶向药物干扰酪氨酸激酶信号转导，可以防止MDSCs的聚集和Treg的抑制活性，从而提高基于免疫的治疗的有效性。我们发现，肿瘤微环境中炎症反应与免疫抑制的调节所需的白细胞亚群可以通过舒尼替尼治疗进行调节。我们推测，阻断受体酪氨酸激酶激活途径不仅可以恢复Treg抑制功能和Foxp3基因的表达，还可以刺激Th17和Th1的炎症反应。1)研究酪氨酸激酶抑制剂(TKI)在体内外调节Treg信号和功能的分子机制；2)研究TKI对Treg向Th17和/或Th1转化的影响；3)研究TKI对人Treg和经TKI治疗的癌症患者的影响及其分子机制。研究苹果酸苏尼替尼的细胞和分子作用机制对未来的临床翻译至关重要。这些研究的成功完成将使人们更好地了解舒尼替尼改变肿瘤微环境和导致免疫转化的作用机制，并可能发现可用于对抗与晚期恶性肿瘤相关的免疫抑制的新的和特定的靶点。免疫抑制的消融将显著提高现有基于免疫的治疗晚期转移性癌症的疗效。 与公共卫生相关：该项目的目标包括：1)确定Sutent在CD4+CD25+FoxP3+T调节细胞中的直接靶点和调节机制；2)确定与Sutent具有类似或更强作用的酪氨酸激酶抑制剂；3)研究Sutent介导T调节细胞向其他CD4谱系转化的机制；4)研究Sutent对癌症患者人类T调节细胞的影响。

DESCRIPTION (provided by applicant): A growing body of evidence suggests that host immune cells with a suppressive phenotype pose a significant hurdle to successful immune enhancing therapy for cancer. Among the suppressor cells, T regulatory cells (Tregs) and myeloid-derived suppressor cells (MDSCs) have been shown to increase significantly in hosts with advanced malignancies. Previously, we found that the growth of various carcinomas induced a significant increase in the numbers of MDSC and Treg in tumor, spleen, and bone marrow. More interestingly, we have demonstrated that MDSC can mediate suppression of the tumor-specific T-cell response through the induction of T-cell anergy and the development of Treg in tumor-bearing mice. These results provide strong evidence of the in vivo immune suppressive functions of MDSC and Treg in tumor-bearing host. To achieve persistent anti-tumor immunity and to improve the efficacy of immunomodulatory therapy, tumor-induced immune suppression must be investigated and overcome. Our studies indicate that targeted pharmacological disruption of tyrosine kinase signaling through the use of a small molecule inhibitor (sunitinib malate; Sutent(r)) can prevent the accumulation of MDSCs and the suppressive activity of Treg, thereby improving the efficacy of immune-based therapy. We have found that leukocyte subsets required for the regulation of inflammatory response vs. immune suppression in the tumor microenvironment can be modulated by sunitinib treatment. We hypothesize that disruption of the receptor tyrosine kinase activation pathway may not only revert Treg suppressive function and Foxp3 gene expression but also stimulate Th17 and Th1 inflammatory responses. Three specific aims will be pursued: 1) To study the molecular mechanisms underlying the regulatory effect of tyrosine kinase inhibitors (TKIs) on Treg signaling and function in vitro and in vivo; 2) To study the effect of TKI on the conversion of Treg into Th17 and/or Th1; 3) To study the effect of TKI, on human Treg and in TKI treated cancer patients, and the underlying molecular mechanisms. Studies of the cellular and molecular mechanisms of action utilized by sunitinib malate are critically important for future clinical translation. Successful completion of these studies will result in a better understanding of the mechanisms of action employed by sunitinib to alter the tumor microenvironment and result in immune conversion and may lead to the discovery of novel and specific targets that can be used to combat the immune suppression associated with advanced malignancies. The ablation of immune suppression should significantly augment the efficacy of existing immune-based therapies for treatment of advanced metastatic cancer. PUBLIC HEALTH RELEVANCE: The goal of this project includes 1) Identify the direct targets and regulation mechanisms of Sutent in CD4+CD25+FoxP3+ T regulatory cells; 2) Identify tyrosine kinase inhibitors that have a similar or stronger effect than Sutent; 3) Study the mechanisms underlying the conversion of T regulatory cells to other CD4 lineages mediated by Sutent; 4) Study the effect of Sutent on human T regulatory cells in cancer patients.