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 ...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.展开更多
基金supported by the National Key Research and Development Program of China(2023YFC2506400 and 2020YFA0112300)the National Natural Science Foundation of China(82230103,82073267,W2431054,81930075,and 82372689)+2 种基金“Ten Thousand Plan”-National High-Level Talents Special Support Plan(WR-YK5202101)Program for Outstanding Leading Talents in Shanghai,Program for Outstanding Medical Academic Leader in Shanghai(2019LJ04)Program of Shanghai Academic/Technology Research Leader(20XD1400700)。
文摘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.
