寻找更有效和低毒副作用的免疫检查点新分子成为肿瘤免疫治疗的焦点。膜蛋白PIK3IP1是PI3K/AKT通路抑制分子，已有研究显示其是肿瘤抑制蛋白，但免疫微环境中作用不明。本课题组前期研究显示PIK3IP1特异性表达于T细胞为主的免疫细胞，且随免疫激活改变；PIK3IP1可抑制T细胞增殖及效应功能；其基因缺失可自发炎症，KO鼠对新抗原有更强的T细胞反应，上述过程伴有Treg和Th17的比例变化。由此提出假说：PIK3IP1是新的免疫检查点分子，其可抑制T淋巴细胞抗肿瘤反应而影响肿瘤生长，这一过程可由Treg/Th17失衡介导。本研究拟利用前期获得的PIK3IP1单抗及敲除鼠，以黑色素瘤和结肠癌为肿瘤模型，以4NQO诱导口腔黏膜癌变为癌前模型，全面评估PIK3IP1对肿瘤抗原特异性反应和肿瘤生长的影响及治疗效能，及依赖Treg/Th17失衡发生的机制，研究有望为肿瘤免疫治疗提供新靶点。

Searching for the new immune checkpoint and develop its inhibitor for the anticipation of better curative effect and lower side effect have become the focus of tumor immune therapy. The membrane protein PIK3IP1 is an inhibitor of P13K/AKT pathway and the related research focused on the tumor epithelium indicated that it’s an inhibitory protein. However, whether it also has effect on immune cells and tumor has not yet been identified. Our early research indicated that PIK3IP1 specifically expressed on immune cells like T cells. And the expression pattern can change with the different activation status in vivo and in vitro. PIK3IP1 can inhibit the proliferation and function of T cells in vivo. It also has blocking effect in vitro and promote the proliferation of T cells. PIK3IP1 knock-out mice show that the loss of the gene can induce innate immune response and inflammation, and the KO mice has more intense T cell reaction towards antigens. Meanwhile, PIK3IP1 can promote iTreg, and the changes in Treg and Th17 are related to the phenomenon described above. Based on the results we’ve achieved, we come up with the hypothesis that PIK3IP1 is a new immune checkpoint. It can inhibit the anti-tumor function of T cells and thus affect the growth of the tumors. This process is driven by the imbalance of Treg and Th17 cells. For the purpose of comprehensively evaluating the effect of PIK3IP1 on tumor antigen specific reaction and effect on tumor growth, we plan to use the anti-mouse monoclonal antibody of PIK3IP1 and the PIK3IP1 knock-out mice that we achieved earlier to build the tumor model based on melanoma and colorectal cancer, as well as the pre-cancerous lesion based on the tumorogenisis of oral mucosa induced by 4NQO. We also plan to identify the receptor or ligand that it interacts with, and further generate the PIK3IP1, Treg and Th17 cross knock-out mice in order to decide whether the phenomenon is related to the imbalance of Treg and Th17.This study is expected to provide a new target and idea in tumor immune therapy.