Mechanisms of Tumor Protection for T Cells by Hypoxia

描述(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是有限的。这项建议的总体目标是了解肿瘤保护的机制，并完成对肿瘤保护免疫抑制分子的靶向消除。为了使新的肿瘤免疫疗法更有效，这是至关重要的。这一提议的中心假设是，低氧肿瘤组织中的肿瘤细胞受到保护，使其免受免疫损伤，因为抗肿瘤T细胞被至少两种低氧依赖机制联合作用而失活：(1)由低氧肿瘤产生的细胞外腺苷通过其表面A2A和A2B腺苷受体的信号抑制T细胞；(2)低氧诱导转录因子1-α(HIF-1α)，它调控参与肿瘤低氧免疫抑制效应的基因的表达。我们的初步结果--发现A2A腺苷受体失活的小鼠对大肿瘤的排斥反应大大改善--有力地支持了这一假说。在这里，我们计划通过使用最近发展起来的几只T细胞特异性缺失A2A受体、A2B受体和HIF-1α基因的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通过内源性和过继转移的抗肿瘤T细胞在不同的CD8+T细胞介导的排斥反应模型中进行测试。我们预计，这些分子的靶向缺失将使抗肿瘤T细胞在肿瘤微环境中抵抗抑制，从而促进肿瘤的破坏。拟议的研究可能通过将复杂的肿瘤微环境减少到只对三个分子-A2A受体、A2B受体和HIF-1α-进行易于处理的遗传、免疫学和生化分析来对其进行解剖，并可能为改进癌症免疫治疗提供一种新的可行的策略。

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.