Regulation of Tumor Microenvironment in Cancer

描述（由申请人提供）：近年来，癌症免疫疗法的进展使得在用各种类型的癌症免疫疗法治疗的患者中诱导肿瘤特异性免疫应答成为可能。然而，尽管取得了这些成功，但从这些治疗中临床获益的患者比例仍然很小。很明显，肿瘤微环境可以提供保护肿瘤，甚至针对有效的细胞毒性T细胞（CTL）反应。与肿瘤微环境相关的炎症在肺癌的发生和发展中起着重要作用。在炎症反应的背景下，骨髓细胞是主要招募的效应物。活性氧（ROS）和氮（RNS）物质的产生是所有活化的骨髓细胞的主要特征之一。过氧化亚硝酸根自由基（PNT）的形成是超氧阴离子与一氧化氮相互作用的主要结果。酪氨酸残基的硝化长期以来被认为是PNT活性的标志。此外，PNT可以直接与半胱氨酸、蛋氨酸和色氨酸反应。大量的研究表明，高水平的硝基酪氨酸（NT）在肺癌。最近，我们提出了一个新的概念，可以解释炎症在肿瘤逃逸中的作用。肿瘤浸润性骨髓细胞，特别是骨髓来源的抑制细胞，可以诱导肿瘤细胞上的MHC I类分子硝化，使它们不能有效地结合和保留肽，从而使肿瘤细胞对抗原特异性CTL具有抗性。这一概念表明，即使通过疫苗、T细胞转移或检查点抑制剂产生了针对肿瘤相关抗原的有效CTL应答，肿瘤也可能逃脱免疫控制。它还表明，这种逃避可以减少通过使用ROS或RNS的药理学抑制剂阻断PNT的生产。基于我们先前和初步的数据，我们提出抑制肿瘤微环境中的ROS和RNS可以增强癌症免疫治疗的效果。在本申请中，我们将测试这一假设。 具体目标1.确定过亚硝酸盐对肿瘤逃逸的影响机制; 具体目标2。在小鼠肿瘤模型中确定阻断性PD 1抗体与新型三萜类RTA 408的联合收割机作用; 具体目标3。探讨肺肿瘤组织中活性氧和活性氮水平升高的临床意义。

DESCRIPTION (provided by applicant): In recent years, advances in cancer immunotherapy make it possible to induce tumor-specific immune responses in patients treated with various types of cancer immunotherapy. However, despite these successes, the proportion of patients who benefit clinically from these treatments remains small. It is clear that the tumor microenvironment may provide protection of tumors even against potent cytotoxic T cell (CTL) responses. Inflammation associated with the tumor microenvironment plays an important role in the development and progression of lung cancer. In the context of an inflammatory response myeloid cells are the primary recruited effectors. Production of reactive oxygen (ROS) and nitrogen (RNS) species is one of the major characteristics of all activated myeloid cells. The formation of the free radical peroxynitrite (PNT) is the main result of interaction between superoxide and nitric oxide. Nitration of tyrosine residues has long been recognized as a marker of PNT activity. In addition, PNT can react directly with cysteine, methionine and tryptophan. A substantial number of studies have demonstrated high levels of nitrotyrosine (NT) in lung cancer. Recently, we have proposed a novel concept that may explain the role of inflammation in tumor escape. The tumor-infiltrating myeloid cells, particularly myeloid-derived suppressor cells, can induce nitration of MHC class I molecules on tumor cells, making them unable to effectively bind and retain peptides and thus rendering the tumor cells resistant to antigen-specific CTLs. This concept suggests that tumors may escape immune control even if potent CTL responses against the tumor-associated antigens were generated either by vaccines, T-cell transfer, or checkpoint inhibitors. It also suggests that this escape can be diminished by blocking the PNT production using pharmacological inhibitors of ROS or RNS. Based on our previous and preliminary data we propose that inhibition of ROS and RNS in the tumor microenvironment can enhance the effect of cancer immune therapy. In this application we will test this hypothesis. Specific aim 1. To determine the mechanism of peroxynitrite effects on tumor escape; Specific aim 2. To determine in mouse tumor models the combine effect of a blocking PD1 antibody with a novel triterpenoid RTA 408; Specific aim 3. To determine clinical significance of up-regulation of reactive oxygen and nitrogen species in lung tumors.