Regulation of Tumor Microenvironment in Cancer

描述（申请人提供）：近年来，癌症免疫治疗的进展使得在接受各种类型的癌症免疫治疗的患者中诱导肿瘤特异性免疫反应成为可能。然而，尽管取得了这些成功，从这些治疗中临床受益的患者比例仍然很小。很明显，肿瘤微环境甚至可以为肿瘤提供保护，甚至抵抗有效的细胞毒性 T 细胞 (CTL) 反应。与肿瘤微环境相关的炎症在肺癌的发生和进展中起着重要作用。在炎症反应的背景下，骨髓细胞是主要招募的效应细胞。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。自由基过氧亚硝酸盐（PNT）的形成是超氧化物和一氧化氮之间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还可与半胱氨酸、蛋氨酸和色氨酸直接反应。大量研究表明，肺癌中硝基酪氨酸 (NT) 水平较高。最近，我们提出了一个新概念，可以解释炎症在肿瘤逃逸中的作用。肿瘤浸润的骨髓细胞，特别是骨髓源性抑制细胞，可以诱导肿瘤细胞上MHC I类分子硝化，使其无法有效结合和保留肽，从而使肿瘤细胞对抗原特异性CTL产生抵抗。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针对肿瘤相关抗原的有效 CTL 反应，肿瘤也可能逃脱免疫控制。它还表明，可以通过使用 ROS 或 RNS 药理学抑制剂阻断 PNT 的产生来减少这种逃逸。根据我们之前的初步数据，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。在此应用中，我们将测试这个假设。 具体目的 1. 明确过氧亚硝酸盐影响肿瘤逃逸的机制； 具体目标 2. 在小鼠肿瘤模型中确定阻断性 PD1 抗体与新型三萜类 RTA 408 的联合作用； 具体目标 3. 确定肺部肿瘤中活性氧和氮物种上调的临床意义。

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.