Myeloid suppressor cell-mediated immune suppression of tumor specific T cells

肿瘤细胞通过各种机制逃避免疫系统的攻击，包括免疫逃避 和/或免疫抑制。为了利用免疫调节疗法达到更好的治疗效果， 研究肿瘤诱导的肿瘤特异性免疫抑制的机制是重要的。 T细胞应答。我们发现，各种癌症的生长导致了显著的增加 肿瘤浸润性白细胞(TIL)、脾和骨髓中髓系抑制细胞(MSC)数量 携带肿瘤的小鼠。我们假设MSC局部抑制肿瘤特异性T细胞反应 在体内灭活肿瘤特异性T细胞反应。初步结果支持我们的假设。 在我们之前提交的文件中提出的，并表明已排序的Gr-1+CD115+MSC从 荷瘤小鼠的脾和骨髓对产生肿瘤抗原的干扰素-γ有明显的抑制作用 激活T细胞，显著降低T细胞IL-2的表达，诱导IL-10的表达， 转化生长因子-β、FoxpS和Tob，并诱导无能的T调节细胞(Treg)的发育 而且很压抑。过继转移的肿瘤抗原特异性T细胞的克隆性扩增 发生在肿瘤生长的早期阶段，但适应性地抑制了扩张 转接的MSC。在后来的时间点上，荷瘤小鼠产生了与 扩增的肿瘤抗原特异性T细胞中FoxpS和Tob的表达此外，领养 分选的Gr-1+CD115+MSC的转移，而不是Gr-rCD115‘或Gr-1+CD115“细胞的转移可以诱发肿瘤 受体荷瘤小鼠的特异性无能和Treg发育。这些结果提供了 体内MSC在肿瘤的建立中具有免疫调节功能的有力证据- 特异性耐受性与Treg的发展。以实现持久的抗肿瘤免疫，并 提高免疫调节治疗效果，肿瘤诱导的免疫抑制必须 克服这一点以实现有效的T细胞反应。我们将追求三个具体目标来理解 MSC积聚的调控机制及其在荷瘤中的体内抑制作用 小鼠：1)研究荷瘤小鼠骨髓间充质干细胞蓄积和分化的机制 2)探讨MSC介导的肿瘤特异性T细胞灭活机制。 3)防止MSC的蓄积，阻断其免疫失活机制，从而 改进免疫调节癌症疗法治疗晚期肿瘤。成功完成这些任务 研究将有助于更好地理解肿瘤介导的免疫机制。 由MSC抑制。这些信息将被用作制定一项 一种新的治疗方式，将抵消与晚期癌症相关的免疫抑制 恶毒。消融MSC介导的抑制应显著增强我们的疗效 晚期癌症患者的免疫激活方案(IL-12基因传递加4-IBB激活)。

Tumor cells escape attack from the immune system through various mechanisms, including immune evasion and/or immune suppression. In order to achieve better therapeutic effects using immune modulatory therapy, it is important to study the mechanisms underlying tumor-induced immunosuppression of the tumor-specific T cell response. We found that the growth of various carcinomas induces a significant increase in the numbers of myeloid suppressor cells (MSC) in tumor infiltrating leukocytes (TILs), spleen, and bone marrow of tumor-bearing mice. We hypothesize that MSC suppress the tumor-specific T cell response locally and inactivate tumor-specific T cell response in vivo. The preliminary results support the hypotheses we proposed in our previous submission and indicate that sorted Gr-1+CD115+ MSC isolated from spleen and bone marrow of tumor-bearing mice drastically inhibit IFN-y-producing tumor antigen- activated T cells, significantly reduce expression of IL-2 by T cells, induce expression of IL-10, TGF-p, FoxpS, and Tob, and induce the development of T regulatory cells (Treg) that are anergic and suppressive. Clonal expansion of adoptively transferred tumor antigen-specific T cells occurred during an early stage of tumor growth, but expansion is suppressed by adaptively transferred MSC. At a later time point, tumor-bearing mice developed tolerance associated with FoxpS and Tob expression in the expanded tumor antigen-specific T cells. Furthermore, adoptive transfer of sorted Gr-1+CD115+ MSC, but not Gr-rCD115'or Gr-1+CD115" cells, can induce tumor specific anergy and Treg development in recipient tumor-bearing mice. These results provide strong evidence of an immunoregulatoryfunction for MSC in vivo in the establishment of tumor- specific tolerance and the development of Treg. To achieve persistent anti-tumor immunity and to improve the therapeutic effect of immunomodulatory treatments, tumor-induced immunosuppression must be overcome to allow for an effective T cell response. Three specific aims will be pursued to understand the mechanisms regulating MSC accumulation and the in vivo suppressive function of MSC in tumor bearing mice: 1) to study the mechanisms underlying the accumulation and differentiation of MSC in tumor-bearing mice; 2) to investigate the mechanisms of MSC-mediated tumor specific T cell inactivation in vitro and in vivo; and 3) to prevent the accumulation of MSC and to block their immune inactivation mechanisms, thereby improving immune modulated cancer therapy for treating advanced tumors. Successful completion of these studies will result in a better understanding of the mechanisms underlying tumor-mediated immune suppression by MSC. This information will be utilized as the scientific foundation for the development of a novel therapeutic modality that would counteract the immune suppression associated with advanced malignancy. The ablation of MSC-mediated suppression should significantly augment the efficacy of our immune activation protocol (IL-12 gene delivery plus 4-IBB activation) for patients with advanced cancer.