过往研究表明，T细胞耗竭可能是机体无法持续杀灭肿瘤的重要原因之一，Tox可能是调控耗竭CD8+T细胞（TEX）的关键因素。本团队前期实验结果证实口咽鳞癌中存在两群特异表达Tox的“祖细胞样”和“终末”TEX，同时HPV+口咽鳞癌患者的“祖细胞样”TEX比例更高且预后更好。因此，我们推测在口咽鳞癌中，Tox可能通过调控Slamf6、Tcf7、Pdcd1等下游基因表达影响“祖细胞样”和“终末”TEX的分化命运，进而影响患者预后。本研究拟通过单细胞测序技术、体外细胞实验和敲除CD8T细胞Tox基因的小鼠实验，首次验证Tox在口咽鳞癌的“祖细胞样”和“终末”TEX分化命运中的作用；探究敲除Tox对口咽鳞癌小鼠TEX耗竭命运逆转和抗肿瘤的效果；阐明HPV+和HPV-这两类口咽鳞癌之间TEX的差异和相关预后差异。本研究探索口咽鳞癌CD8+T细胞耗竭机制及其预后相关性，将有助于寻找新的免疫治疗策略。

Recent studies found that the exhausted CD 8+ T cell (TEX) might be the reason of tumor persistent existing, and Tox might be a key factor in regulating CD8+ T cell exhaustion program. Our previous results of single cell sequence revealed that Tox also specifically expressed in two clusters of "progenitor-like" and "terminal" TEX in oropharyngeal squamous cell carcinoma (OPSCC). Besides, our results showed that patients with HPV positive OPSCC had higher rate of "progenitor-like" TEX and better outcomes. Therefore, we speculate that Tox controls the differentiation fate of "progenitor-like" and "terminal" TEX among HPV+ /HPV- OPSCC patients by regulating the expression of downstream genes such as Slamf6, Tcf7 and Pdcd1. This is the first study that intends to verify the role of Tox in the differentiation fate of "progenitor-like" and "terminal" TEX in OPSCC using single-cell sequencing technology, in vitro cell restimulation experiments, and Tox knockout mice; to explore the effects of Tox knockout on the renew of TEX and their anti-tumor effects in OPSCC mice; and to compare the difference of TEX and their related outcomes between HPV+ and HPV- OPSCC. This study will help explore the exhaustion mechanism and their related prognosis for OPSCC, and help explore new immunotherapy strategies.