Ma Xinyue, Wang Qiuman, Sun Chenggong, Agarwal Indu, Wu Huan, Chen Jingying, Zhao Chen, Qi Gonghua, Teng Qiuli, Yuan Cunzhong, Yan Shi, Peng Jiali, Li Rongrong, Song Kun, Zhang Qing, Kong Beihua
Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Ji'nan, Shandong 250012, P.R. China; Gynecology Oncology Key Laboratory, Qilu Hospital of Shandong University, Ji'nan, Shandong 250012, P.R. China.
Department of Pathology, Northwestern University, Chicago, IL 60208, USA.
Cell Rep. 2023 Aug 29;42(8):112944. doi: 10.1016/j.celrep.2023.112944. Epub 2023 Aug 10.
Immune checkpoint blockade (ICB) therapies display clinical efficacy in microsatellite instable (MSI) endometrial cancer (EC) treatment, the key mechanism of which is reversing T cell exhaustion and restoration of anti-tumor immunity. Here, we demonstrate that transcription factor 19 (TCF19), one of the most significantly differentially expressed genes between MSI and microsatellite stable (MSS) patients in The Cancer Genome Atlas (TCGA)-EC cohort, is associated with poor prognosis and immune exhaustion signature. Specifically, TCF19 is significantly elevated in MSI EC, which in turn promotes tripartite motif-containing 14 (TRIM14) transcription and correlates with hyperactive signaling of the TANK-binding kinase 1 (TBK1)-interferon regulatory factor 3 (IRF3)-interferon β (IFN-β) pathway. The TCF19-TRIM14 axis promotes tumorigenicity under non-immunological background, and the enhanced downstream secretion of IFN-β facilitates CD8 T cell exhaustion through cell differentiation reprogramming. Finally, using humanized models, we show that a combination of TCF19 inhibition and ICB therapy demonstrates more effective anti-tumor responses. Together, our study indicates that targeting TCF19 is a potent strategy for alleviating CD8 T cell exhaustion and synergizing with ICB in tumor treatment.
免疫检查点阻断（ICB）疗法在微卫星不稳定（MSI）子宫内膜癌（EC）治疗中显示出临床疗效，其关键机制是逆转T细胞耗竭并恢复抗肿瘤免疫力。在此，我们证明转录因子19（TCF19）是癌症基因组图谱（TCGA）-EC队列中MSI与微卫星稳定（MSS）患者之间差异表达最显著的基因之一，与预后不良和免疫耗竭特征相关。具体而言，TCF19在MSI EC中显著升高，进而促进含三联基序的蛋白14（TRIM14）转录，并与TANK结合激酶1（TBK1）-干扰素调节因子3（IRF3）-干扰素β（IFN-β）通路的高活性信号传导相关。在非免疫背景下，TCF19-TRIM14轴促进肿瘤发生，且下游增强分泌的IFN-β通过细胞分化重编程促进CD8 T细胞耗竭。最后，利用人源化模型，我们表明抑制TCF19与ICB疗法联合使用可显示出更有效的抗肿瘤反应。总之，我们的研究表明，靶向TCF19是减轻CD8 T细胞耗竭并在肿瘤治疗中与ICB协同作用的有效策略。
