Regulation of Tumor Microenvironment in Cancer

癌症中肿瘤微环境的调节

• 批准号: 8856524
• 负责人: SCOTT J. ANTONIA
• 金额: $ 37.36万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8856524
• 关键词: 3-nitrotyrosine; Address; Antibodies; Antigen Presentation; Antigens; Apoptosis; Binding; CD8 Antigens; Cancer Patient; Cell physiology; Characteristics; Clinical; Cysteine; Cytotoxic T-Lymphocytes; Data; Development; Free Radical Formation; Health; Histocompatibility Antigens Class I; Immune; Immune response; Immunotherapy; Inflammation; Inflammatory Response; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Methionine; Methods; Modeling; Mus; Myelogenous; Myeloid Cells; Nitric Oxide; Nitrogen; Non-Small-Cell Lung Carcinoma; Oxygen; Patients; Peptide/MHC Complex; Peptides; Peripheral; Peroxonitrite; Pharmaceutical Preparations; Phase I/II Trial; Play; Production; Proteins; Recruitment Activity; Regulation; Resistance; Role; Sampling; Signal Transduction; Superoxides; Suppressor-Effector T-Lymphocytes; Surface; T cell response; T-Cell Receptor; T-Lymphocyte; Testing; Tissues; Tryptophan; Tumor Antigens; Tumor Escape; Tyrosine; Up-Regulation; Vaccines; base; cancer cell; cancer immunotherapy; clinically relevant; clinically significant; granulocyte; improved; inhibitor/antagonist; killings; macrophage; mouse model; neoplastic cell; nitration; novel; novel strategies; pre-clinical; receptor; response; success; tumor; tumor microenvironment

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.

描述（由申请人提供）：近年来，癌症免疫疗法的进展使得患有各种类型的癌症免疫疗法的患者诱导肿瘤特异性免疫反应。但是，尽管取得了这些成功，但从这些治疗中受益的患者比例仍然很小。显然，肿瘤微环境即使免受有效的细胞毒性T细胞（CTL）反应，也可以保护肿瘤。与肿瘤微环境相关的炎症在肺癌的发展和发展中起着重要作用。在炎症反应的背景下，髓样细胞是主要募集效应子。活性氧（ROS）和氮（RNS）物种的产生是所有活化的髓样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一直被认为是PNT活性的标志。另外，PNT可以直接与半胱氨酸，蛋氨酸和色氨酸反应。大量研究表明，肺癌中的硝基酪氨酸（NT）高水平。最近，我们提出了一个新颖的概念，可以解释炎症在肿瘤逃生中的作用。肿瘤浸润的髓样细胞，尤其是髓样衍生的抑制细胞，可以诱导肿瘤细胞上MHC I类分子的硝化，使其无法有效地结合和保留肽，从而使肿瘤细胞具有抗抗原特异性CTL的抗肿瘤细胞。这个概念表明，即使疫苗，T细胞转移或检查点抑制剂对与肿瘤相关的抗原产生有效的CTL反应也可能逃脱免疫控制。这也表明，可以使用ROS或RNS的药理抑制剂阻止PNT产生这种逃生。根据我们以前的和初步数据，我们建议抑制ROS和RN在肿瘤微环境中可以增强癌症免疫治疗的作用。在此应用程序中，我们将检验该假设。 具体目的1。确定过氧亚硝酸盐对肿瘤逃生的作用的机制； 具体目的2。要在小鼠肿瘤模型中与新型三萜RTA 408的封闭PD1抗体的联合效应； 具体目的3。确定肺部肿瘤中活性氧和氮种上上调的临床意义。