Correction of dendritic cells defects in cancer

描述(由申请人提供)：尽管前景看好，但已在临床试验中测试的免疫治疗策略尚未为大多数患者带来切实的好处。许多临床试验已经证明，成功地产生了针对肿瘤特异性抗原的免疫反应。然而，在大多数患者中，这些反应与临床反应无关。免疫抑制的肿瘤微环境阻碍了细胞毒性T细胞(CTL)识别和清除肿瘤，这是限制免疫治疗效果的主要因素之一。Parent Grant致力于了解髓系抑制细胞(MDSC)诱导T细胞缺陷的机制。在项目目标的实施过程中，我们发现MDSC介导的T细胞耐受的主要机制之一是由于MDSC增加了活性氧(ROS)和氮(RNS)物种的产生而导致TCR的翻译后修饰。在目前的修订中，我们建议扩大父母补助金的范围。根据我们新的初步数据，我们认为，在肿瘤微环境中，过氧亚硝酸盐和其他ROS通过渗透髓系细胞或肿瘤细胞而产生的影响比仅仅对T细胞的影响要广泛得多。我们认为过氧亚硝酸盐和ROS导致肿瘤细胞上表达的MHC I类分子和/或由这些MHC I类分子呈递的肿瘤特异性多肽发生修饰。这将使针对肿瘤抗原衍生多肽的CTL无法识别和消除肿瘤细胞。因此，即使癌症免疫治疗产生了有效的抗原特异性CTL，或者如果这些CTL是在体外产生的，然后过继转移到患者身上，MHC I类分子的翻译后修饰也会抵消任何可能的抗肿瘤作用。由于不同患者的髓系细胞浸润和过氧亚硝酸盐产生水平不同，这可能是患者过继转移T细胞或疫苗治疗结果不同的原因。在这项拟议的研究中，我们计划对这一假设进行实验验证。我们还将测试使用新型化合物RTA 402逆转过氧亚硝酸盐影响的可能性，该化合物已被证明在阻断活性氧物种和减少过氧亚硝酸盐产生方面具有高水平的活性。我们提出以下特定目的：特定目的：1.在肺癌动物模型中，明确肿瘤逃逸与活性氧和氮物种过度产生相关的机制。具体目的2.在肺癌的临床前模型中，确定新的治疗化合物逆转过氧亚硝酸盐诱导的肿瘤逃逸细胞毒性T细胞的能力。 公共卫生相关性：拟议的研究将调查肿瘤逃逸的新机制，与肿瘤组织中过氧亚硝酸盐的产生增加有关。我们将检验新的假设，即细胞毒性T淋巴细胞无法识别和消除肿瘤细胞的部分原因是过氧亚硝酸盐诱导的对肿瘤细胞表面MHC I类和/或多肽表位的修饰。我们将探讨这一现象的机制，并测试几种消除这种影响的治疗方法，以期提高癌症免疫治疗的效果。

DESCRIPTION (provided by applicant): Despite high promise the immunotherapeutic strategies that have been tested in clinical trials have not yet delivered tangible benefits to most patients. Numerous clinical trials have demonstrated successful generation of immune responses against tumor-specific antigens. However, these responses have not been associated with clinical responses in most patients. It has become increasingly clear that one of the major factors that limit the effectiveness of immunotherapy is the immunosuppressive tumor microenvironment, which prevents cytotoxic T cells (CTL) from recognizing and eliminating tumor. Parent grant is focused to understanding the mechanisms of T-cell defects induced by myeloid-derived suppressor cells (MDSC). In a course of implementation of the goals of the project we found that one of the major mechanisms of MDSC mediated T-cell tolerance was a posttranslational modification of TCR caused by increased production of reactive oxygen (ROS) and nitrogen (RNS) species by MDSC. In current revision we propose to expand the scope of the parent grant. Based on our new preliminary data we propose that effect of peroxynitrite and other ROS produced in tumor microenvironment by infiltrating myeloid cells or tumor cells is much broader than just effect on T cells. We suggest that peroxynitrite and ROS cause modification of MHC class I molecules expressed on tumor cells and/or tumor-specific peptides presented by those MHC class I molecules. This would make CTLs specific for tumor antigen derived peptides unable to recognize and eliminate tumor cells. Thus, even if cancer immunotherapy results in the generation of potent antigen-specific CTLs or if these CTLs are generated in vitro and then adoptively transferred to patients, post-translational modification of MHC class I would negate any possible antitumor effect. Since the level of myeloid cell infiltration and peroxynitrite production varies from patient to patient this may account for variable results of patients' treatment with adoptive transfer of T cells or vaccines. In the proposed study we plan to experimentally test this hypothesis. We will also test the possibility of reversing the effect of peroxynitrite by employing the novel compound RTA 402, which has been demonstrated to have a high level of activity in blocking reactive oxygen species and decreasing peroxynitrite production. We propose the following specific aims: Specific aim 1. To identify the mechanism of tumor escape associated with hyperproduction of reactive oxygen and nitrogen species in animal models of lung cancer. Specific aim 2. To determine in preclinical models of lung cancer the ability of novel therapeutic compounds to reverse the peroxynitrite-inducible tumor escape from cytotoxic T cells. PUBLIC HEALTH RELEVANCE: Proposed research will investigate novel mechanism of tumor escape associated with increased production of peroxynitrite in tumor tissues. We will test novel hypothesis that inability of cytotoxic T lymphocytes to recognize and eliminate tumor cells was caused in part by peroxynitrite inducible modifications of MHC class I and/or peptide epitopes on the surface of tumor cells. We will investigate the mechanism of this phenomenon and test several therapeutic approaches to eliminate this effect with goal to enhance the effect of cancer immunotherapy.