Abstract
Tumors employ various strategies to evade immune surveillance. Central nervous system (CNS) has multiple features to restrain immune response. Whether tumors and CNS share similar programs of immunosuppression is elusive. Here, we analyze multi-omics data of tumors from HER2+ breast cancer patients receiving trastuzumab and anti-PD-L1 antibody and find that CNS-enriched N-acetyltransferase 8-like (NAT8L) and its metabolite N-acetylaspartate (NAA) are overexpressed in resistant tumors. In CNS, NAA is released during brain inflammation. NAT8L attenuates brain inflammation and impairs anti-tumor immunity by inhibiting cytotoxicity of natural killer (NK) cells and CD8+ T cells via NAA. NAA disrupts the formation of immunological synapse by promoting PCAF-induced acetylation of lamin A-K542, which inhibits the integration between lamin A and SUN2 and impairs polarization of lytic granules. We uncover that tumor cells mimic the anti-inflammatory mechanism of CNS to evade anti-tumor immunity and NAT8L is a potential target to enhance efficacy of anti-cancer agents.
肿瘤采用各种策略逃避免疫监视。中枢神经系统（CNS）具有抑制免疫反应的多种特征。肿瘤和中枢神经系统是否共享类似的免疫抑制程序尚不明确。在这里，我们分析了接受曲妥珠单抗和抗PD-L1抗体治疗的HER2+乳腺癌患者肿瘤的多组学数据，发现中枢神经系统富含的N-乙酰转移酶8样（NAT8L）及其代谢产物N-乙酰天冬氨酸（NAA）在耐药肿瘤中过度表达。在中枢神经系统中，NAA 在脑部炎症期间释放。NAT8L通过NAA抑制自然杀伤（NK）细胞和CD8+ T细胞的细胞毒性，从而减轻脑部炎症并损害抗肿瘤免疫。NAA通过促进PCAF诱导的片层蛋白A-K542乙酰化破坏免疫突触的形成，从而抑制片层蛋白A和SUN2之间的整合，并损害裂解颗粒的极化。我们发现肿瘤细胞模仿中枢神经系统的抗炎机制来逃避抗肿瘤免疫，而NAT8L是提高抗癌药物疗效的潜在靶点。
参考文献
Li Y, Huang M, Wang M, Wang Y, Deng P, Li C, Huang J, Chen H, Wei Z, Ouyang Q, Zhao J, Lu Y, Su S. Tumor cells impair immunological synapse formation via central nervous system-enriched metabolite. Cancer Cell. 2024 Jun 10;42(6):985-1002.e18. doi: 10.1016/j.ccell.2024.05.006.
