| 论文作者 |
Xia, J; Zhang, LX; Zhu, WC; Tu, JCL; Peng, XL; Deng, QD; Li, SQ; He, XY; Dong, HN; Liu, CC; Chen, X; Xu, JH; Ma, W; Xiao, Y; Liu, W; Hu, GH; Jiang, YZ; Chen, CS; Bian, XW; Shao, ZM; Liu, SL |
| 摘要 |
Neurotransmitters are increasingly recognized to play important roles in limiting anti-tumor immunity. N-acetyl-aspartyl-glutamate (NAAG) has been extensively studied in neurological disorders; however, its potential role in restricting anti-tumor immunity has not been investigated. Here, we demonstrated that NAAG or its synthetase RimK-like family member B (RIMKLB) significantly disrupted anti-tumor immunity by rewiring the myeloid progenitor differentiation of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), which in turn promoted breast cancer growth and metastasis. Mechanistically, NAAG sustained the tumor immunosuppressive microenvironment by activating an NR2B-containing NMDA receptor (NR2B-NMDAR)-dependent p38-NOTCH1 axis, and subsequently stimulating tumor cell migration and invasion, as well as inducing PMN-MDSC differentiation and expansion. In mouse models, RIMKLB ablation or NMDAR inhibition enhanced the efficacy of anti-PD-1 therapy and suppressed tumor progression. An analysis of clinical samples revealed that high levels of NAAG and NR2B-NMDAR predicted a poor prognosis in TNBC patients. Collectively, our findings have uncovered a signaling role for tumor-derived NAAG beyond its classic function as a neurotransmitter that can be targeted pharmacologically to enhance immunotherapy against breast cancer. (c) 2024 The Authors. Published by Elsevier B.V. and Science China Press. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
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