2. Academic Validation
  3. Tumor cells impair immunological synapse formation via central nervous system-enriched metabolite

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.
Yihong Li 1,  Min Huang 1,  Minger Wang 2,  Yi Wang 2,  Peng Deng 3,  Chunni Li 3,  Jingying Huang 3,  Hui Chen 4,  Zhihao Wei 3,  Qian Ouyang 3,  Jinghua Zhao 3,  Yiwen Lu 5,  Shicheng Su 6
Affiliations

Affiliations

  • 1 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China.
  • 2 School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.
  • 3 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China.
  • 4 Guangdong Provincial Key Laboratory of Liver Disease Research the Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510630, China.
  • 5 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China. Electronic address: luyw8@mail.sysu.edu.cn.
  • 6 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China; Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; Department of Immunology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China; Biotherapy Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China. Electronic address: sushch@mail.sysu.edu.cn.
PMID: 38821061 DOI: 10.1016/j.ccell.2024.05.006
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.

Keywords

Tumor metabolism; anti-tumor immunity; immune checkpoint blockade; immunological synapse; neuroinflammation.

Figures
Products