中山大学Shicheng Su和Yiwen Lu课题组合作发现，肿瘤细胞通过类似于中枢神经系统（CNS）的机制富集代谢物损害免疫突触的形成。相关论文于2024年5月30日发表在《癌细胞》杂志上。

研究人员分析了接受曲妥珠单抗和抗PD-L1抗体治疗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）蛋白及其代谢产物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在脑部炎症期间累积。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诱导的核纤层A-K542乙酰化破坏免疫突触的形成，从而抑制核纤层A和SUN2之间的结合，并损害裂解颗粒的极化。该研究发现肿瘤细胞利用类似于中枢神经系统的抗炎机制来逃避抗肿瘤免疫，并证明NAT8L是提高抗癌药物疗效的潜在靶点。

据了解，肿瘤采用各种策略逃避免疫监视。中枢神经系统具有抑制免疫反应的多种特征。尚不明确肿瘤和中枢神经系统是否具有类似的免疫抑制机制。

附：英文原文

Title: Tumor cells impair immunological synapse formation via central nervous system-enriched metabolite

Author: Yihong Li, Min Huang, Minger Wang, Yi Wang, Peng Deng, Chunni Li, Jingying Huang, Hui Chen, Zhihao Wei, Qian Ouyang, Jinghua Zhao, Yiwen Lu, Shicheng Su

Issue&Volume: 2024-05-30

Abstract: Tumors employ various strategies to evade immune surveillance. Central nervous system(CNS) has multiple features to restrain immune response. Whether tumors and CNS sharesimilar programs of immunosuppression is elusive. Here, we analyze multi-omics dataof tumors from HER2+ breast cancer patients receiving trastuzumab and anti-PD-L1 antibody and find thatCNS-enriched N-acetyltransferase 8-like (NAT8L) and its metabolite N-acetylaspartate(NAA) are overexpressed in resistant tumors. In CNS, NAA is released during braininflammation. NAT8L attenuates brain inflammation and impairs anti-tumor immunityby inhibiting cytotoxicity of natural killer (NK) cells and CD8+ T cells via NAA. NAA disrupts the formation of immunological synapse by promotingPCAF-induced acetylation of lamin A-K542, which inhibits the integration between laminA and SUN2 and impairs polarization of lytic granules. We uncover that tumor cellsmimic the anti-inflammatory mechanism of CNS to evade anti-tumor immunity and NAT8Lis a potential target to enhance efficacy of anti-cancer agents.

DOI: 10.1016/j.ccell.2024.05.006

Source: https://www.cell.com/cancer-cell/abstract/S1535-6108(24)00169-7