T细胞在肿瘤免疫中起重要作用，过继T细胞治疗是新兴的肿瘤治疗方法。但肿瘤内部的酸性微环境对T细胞的抗肿瘤免疫有抑制作用，我们对于酸性微环境如何影响T细胞功能还知之甚少。OGR1 是感知质子的受体，T细胞高表达OGR1，但OGR1在T细胞中的功能却还未知。我们的前期结果显示OGR1敲除小鼠能抑制肿瘤的生长，这一抑制作用需要T细胞的直接参与。OGR1是潜在的T细胞功能调节者，可能介导了肿瘤酸性微环境中的质子对T细胞的抑制作用。本项目将在现有研究的基础上，利用动物模型、T细胞功能性实验和生化方法，从体内(动物个体)、体外(细胞)和分子机制三个层面深入研究OGR1在T细胞中的功能，特别是OGR1对T细胞抗肿瘤免疫的影响和OGR1在酸性pH对T细胞抑制过程中的作用。在此基础上通过筛选抑制和激活OGR1靶点的小分子，探寻调节OGR1信号通路的途径，为肿瘤的T细胞免疫治疗提供新的思路。

T-cell immunity plays a critical role in controlling tumor development and CD8+ cytotoxic T lymphocytes (CTLs) are key effector cells in antitumor immunity. Adoptive T-cell therapy has shown promise for cancer therapy. Studies over the last few decades have demonstrated that the extracellular pH of solid tumors is acidic, T cells could be extremely sensitive to pH variations. Low extracellular pH suppresses effective T cell antitumoral immune response. However, there is little knowledge about how acidic microenvironments suppress T-cell immunity. OGR1 (ovarian cancer G protein-coupled receptor) is a proton sensor, OGR1 deficient mice are viable and upon gross-inspection appear normal. Unexpectedly, we have found that prostate and melanoma tumor development is significantly inhibited in OGR1 deficient mice. OGR1 is expressed in T cells and infiltration of CD4+ and CD8+ T cells is significantly increased in tumors from ogr1-/- mice compared with tumors from WT mice. Both CD4+ and CD8+ T cells are involved in tumor rejection in ogr1-/- mice, and function as effector cells in tumor rejection. Thus, we hypothesize that OGR1 may regulate T cell functions and mediate low pH induced T cell suppression in tumors, removing OGR1 unleashes the suppressive effect, resulting in activation of T cells and tumor rejection. Hence, the main goal of this proposal is to determine the cellular and molecular mechanisms underlying the functions of OGR1 in T cells pertinent to its role in antitumor immunity. To test our hypotheses, four specific aims are proposed. 1) We will determine the role of OGR1 in T cell mediated antitumor immunity in vivo employing mice models. 2) We will determine cellular mechanisms underlying OGR1's role in T cell mediated antitumor immunity in vitro using T cell functional assay. 3) We will delineate molecular mechanisms underlying OGR1's role in T cells using biochemical approaches. 4) We will screen specific agonists and antagonists of OGR1 based on Ca2+ flux assays and cAMP assays. Our preliminary studies suggest that OGR1, an un-expected and new player in T cells may represent a novel and significant approach to manipulate T cells. This proposed study will offer new insights into effects of acidic tumor microenvironment on T cells. The information gained from this study will also furnish the bases for the development of effective adoptive T cell therapy for cancer patients by targeting OGR1.