摘要
Background The efficacy of anti-programmed cell death protein 1(PD-1)immunotherapy in various cancers,including gastric cancer(GC),needs to be potentiated by more effective targeting to enhance therapeutic efficacy or identifying accurate biomarkers to predict clinical responses.Here,we attempted to identify molecules predicting or/and promoting anti-PD-1 therapeutic response in advanced GC(AGC).Methods The transcriptome of AGC tissues from patients with different clinical responses to anti-PD-1 immunotherapy and GC cells was analyzed by RNA sequencing.The protein and mRNA levels of the major facilitator superfamily domain containing 2A(MFSD2A)in GC cells were assessed via quantitative real-time polymerase chain reaction,Western blotting,and immunohistochemistry.Additionally,the regulation of anti-PD-1 response by MFSD2A was studied in tumor-bearing mice.Cytometry by Time-of-Flight,multiple immunohistochemistry,and flow cytometry assays were used to explore immunological responses.The effects of MFSD2A on lipid metabolism in mice cancer tissue and GC cells was detected by metabolomics.Results Higher expression of MFSD2A in tumor tissues of AGC patients was associated with better response to anti-PD-1 immunotherapy.Moreover,MFSD2A expression was lower in GC tissues compared to adjacent normal tissues,and its expression was inversely correlated with GC stage.The overexpression of MFSD2A in GC cells enhanced the efficacy of anti-PD-1 immunotherapy in vivo by reprogramming the tumor microenvironment(TME),characterized by increased CD8+T cell activation and reduced its exhaustion.MFSD2A inhibited transforming growth factorβ1(TGFβ1)release from GC cells by suppressing cyclooxygenase 2(COX2)-prostaglandin synthesis,which consequently reprogrammed TME to promote anti-tumor T cell activation.Conclusions MFSD2A potentially serves as a predictive biomarker for anti-PD-1 immunotherapy response in AGC patients.MFSD2A may be a promising therapeutic target to potentiate the efficacy of anti-PD-1 immunotherapy by reprogramming
基金
the CAMS Innovation Fund for Medical Sciences,Grant/Award Numbers:2022-I2M-2-004,2021-I2M-1-074
National Natural Science Foundation of China,Grant/Award Numbers:82001677,82102921,82388201
Fundamental Research Funds for the Central Universities,Grant/Award Number:3332021075
Jiangsu Innovative and Entrepreneurial Talent Programme,Grant/Award Number:2020-30084。
