Galectin9（Gal9）是免疫检查点TIM-3的配体，可分泌或由外泌体携带至细胞外，前期工作发现Gal9在鼻咽癌细胞表达上调，并与患者不良预后相关；有研究报道Gal9与T细胞凋亡和功能失衡相关。近期研究发现肿瘤抗原特异性CD8+T细胞的重分化和功能失衡是影响PD-1抗体等免疫检查点阻断治疗临床疗效的关键因素。我们在此基础上提出：肿瘤微环境Gal9可调控CD8+T细胞在鼻咽癌中的重分化和功能状态，且影响PD-1抗体的临床疗效。我们通过高通量的单细胞测序或流式质谱检测鼻咽癌微环境CD8+T细胞重分化亚群的分子特征，结合PD-1单抗II期临床试验筛查PD-1抗体治疗临床疗效评估的分子标志；并通过体外和体内功能实验探索肿瘤微环境Gal9调控CD8+T细胞重分化和功能的分子机制；在鼻咽癌移植瘤模型中验证靶向Gal9对肿瘤生长和预后的治疗作用。希望发现鼻咽癌免疫治疗的新靶点和免疫治疗评估的标志。

Galectin-9 (G9) is a ligand of immune checkpoint TIM-3, which can be secreted or carried by exosome to the outside of the cells. Previous work found that G9 protein is up-regulated in nasopharyngeal carcinoma (NPC) and is associated with poor prognosis; In addition, studies have reported that G9 is associated with T cell apoptosis and dysfunction. Recent studies suggest that tumor antigen-specific CD8+ T cells (TST) have de novo and dysfunction in tumor patients, which are the key factors for the efficacy of PD-1 and other immune checkpoint blockade therapy. Based on the above studies, we propose that G9 protein, which is highly expressed in NPC, could regulate the de novo and functions of CD8+ T cells in tumors and affect the clinical efficacy of PD-1 antibody. Firstly, we plan to screen the molecular characteristics and de novo subsets of CD8+ TST cells from NPC tissues (pre-treatment) by high-dimensional single-cell RNA sequencing or Mass Cytometry, and the levels of serum Gal-9 and exosome carried Gal-9, and circuiting CD8+ T cell subsets are detected and analyzed their clinical relevance in NPC patients. the molecular mechanism of how extracellular G9 regulate the de novo and functions of CD8+ T cell are explored in vitro and in mouse tumor model. We will analyze the correlations between the Gal-9 level and CD8+T cell subsets and the clinical efficacy of PD-1 antibody treatment in NPC patients, to screen the biomarkers to predict the clinical efficacy of PD-1 antibody treatment based on a phase II clinical trial of PD-1 mAb in NPC patients. The treatment effect of targeting Gal-9 combined with tumor-specific CD8+T cells will be analyzed in NPC NOD-SCID mouse model. Totally, our results anticipate to reveal the potential new targets for NPC immunotherapy and find effective biomarkers which can predict the efficacy of PD-1 antibody immunotherapy.