Abstract：
The major histocompatibility complex class I (MHC class I)-mediated tumor antigen processing and presentation (APP) pathway is essential for the recruitment and activation of cytotoxic CD8+ T lymphocytes (CD8+ CTLs). However, this pathway is frequently dysregulated in many cancers, thus leading to a failure of immunotherapy. Here, we report that activation of the tumor-intrinsic Hippo pathway positively correlates with the expression of MHC class I APP genes and the abundance of CD8+ CTLs in mouse tumors and patients. Blocking the Hippo pathway effector Yes-associated protein/transcriptional enhanced associate domain (YAP/TEAD) potently improves antitumor immunity. Mechanistically, the YAP/TEAD complex cooperates with the nucleosome remodeling and deacetylase complex to repress NLRC5 transcription. The upregulation of NLRC5 by YAP/TEAD depletion or pharmacological inhibition increases the expression of MHC class I APP genes and enhances CD8+ CTL-mediated killing of cancer cells. Collectively, our results suggest a crucial tumor-promoting function of YAP depending on NLRC5 to impair the MHC class I APP pathway and provide a rationale for inhibiting YAP activity in immunotherapy for cancer.
摘要：
主要组织相容性复合物I类（MHCI类）介导的肿瘤抗原加工和呈递（APP）途径对于细胞毒性CD8T淋巴细胞（CD8CTL）的募集和激活至关重要。然而,这种通路在许多癌症中经常失调，从而导致免疫疗法的失败。这里,我们报道,在小鼠肿瘤和患者中,肿瘤固有Hippo通路的激活与MHCI类APP基因的表达和CD8+CTL的丰度正相关.阻断Hippo途径效应物Yes相关蛋白/转录增强相关结构域(YAP/TEAD)有效改善抗肿瘤免疫。机械上,YAP/TEAD复合物与核小体重塑和脱乙酰酶复合物协作以抑制NLRC5转录。通过YAP/TEAD消耗或药理学抑制对NLRC5的上调增加了MHCI类APP基因的表达并增强了CD8+CTL介导的对癌细胞的杀伤。总的来说，我们的结果表明,YAP的重要肿瘤促进功能依赖于NLRC5,从而损害MHCI类APP通路,并为在癌症免疫治疗中抑制YAP活性提供了理论基础.
