Mechanisms of Tumor Protection for T Cells by Hypoxia

描述（由申请人提供）：据信，由于抗肿瘤T细胞在实体瘤的微环境中受到抑制，因此有前景的癌症免疫治疗应用的范围受到限制。该提案的总体目标是了解肿瘤保护机制，并实现肿瘤保护免疫抑制分子的靶向消除。这对于使新型肿瘤免疫疗法更有效至关重要。该建议的中心假设是，缺氧癌组织中的肿瘤细胞受到保护而免受免疫损伤，因为抗肿瘤T细胞通过至少两种缺氧依赖性机制的联合作用而失活：（1）由缺氧肿瘤产生的细胞外腺苷通过其表面A2 A和A2 B腺苷受体的信号传导抑制T细胞;和（2）低氧诱导转录因子1-α（HIF-1 α），其控制有助于肿瘤低氧的免疫抑制作用的基因的表达。我们的初步结果--在A2 A腺苷受体失活的小鼠中发现大肿瘤的排斥反应大大改善--强烈支持这一假设。在这里，我们计划通过使用几种最近开发的具有T细胞特异性缺失A2 A受体、A2 B受体和HIF-1 α基因的独特小鼠来进一步阐明这种肿瘤保护机制。免疫原性和弱免疫原性肿瘤将在内源性和过继转移的抗肿瘤T细胞的不同CD 8 + T细胞介导的排斥模型中进行检测。 我们预期这些分子的靶向缺失将使抗肿瘤T细胞对肿瘤微环境中的抑制具有抗性，从而促进肿瘤的破坏。拟议的研究可以通过将其简化为仅对三种分子-A2 A受体，A2 B受体和HIF-1 α-进行可管理的遗传，免疫学和生化分析来解剖复杂的肿瘤微环境，并且还可以提供一种新颖可行的策略来改善癌症免疫治疗。

DESCRIPTION (provided by applicant): It is believed that the scope of promising cancer immunotherapy applications is limited because anti-tumor T cells are inhibited in the microenvironment of solid tumors. The overall goal of this proposal is to understand the mechanism of tumor protection and to accomplish the targeted elimination of tumor-protecting immunosuppressive molecules. This is crucial in order to render novel tumor immunotherapies more effective. The central hypothesis of this proposal is that tumor cells in hypoxic cancerous tissues, protected from immune damage because anti-tumor T cells are inactivated by the combined action of at least two hypoxia-dependent mechanisms: (1) extracellular adenosine produced by the hypoxic tumor inhibits T cells via signaling through their surface A2A and A2B adenosine receptors; and (2) the hypoxia-inducible transcription factor 1-alpha (HIF-1alpha) which governs the expression of genes that contribute to the immunosuppressive effects of tumor hypoxia. Our preliminary results - findings of much improved rejection of large tumors in mice with inactivated A2A adenosine receptor - strongly support this hypothesis. Here we plan to further clarify this mechanism of tumor protection by using several recently developed unique mice with T cell-specific deletion of A2A receptor, A2B receptor, and HIF-1alpha genes. Both immunogenic and weakly immunogenic tumors will be tested in different models of CD8+ T cell-mediated rejection by endogenous and adoptively transferred anti-tumor T cells. We expect that targeted deletion of these molecules will render anti-tumor T cells resistant to inhibition in the tumor microenvironment and, thus, facilitate the destruction of tumors. The proposed studies may allow dissection of the complex tumor microenvironment by reducing it to a manageable genetic, immunological, and biochemical analysis of only three molecules - A2A receptor, A2B receptor, and HIF-1alpha- and may also offer a novel and feasible strategy to improve cancer immunotherapy.