Gastric cancer mesenchymal stem cells via the CXCR2/HK2/PD-L1 pathway mediate immunosuppression
Gastric cancer mesenchymal stem cells via the CXCR2/HK2/PD-L1 pathway mediate immunosuppression
复制标题
胃癌间充质干细胞通过CXCR2/HK2/PD -L1通路介导免疫抑制
DOI：
10.1007/s10120-023-01405-1
复制
发表时间：
2023-06-10
期刊：
影响因子：
7.4
通讯作者：
Zhu，Wei
中科院分区：
文献类型：
--
作者：
Huang，Chao;Chen，Bin;Zhu，Wei
背景：抗PD-1免疫治疗已成为进展期胃癌的重要治疗手段。方法在NPGCD34+或NCGPBMC异种移植模型中，体内观察胃癌间充质干细胞(GCMSCs)在抗PD-1耐药中的作用。此外，我们还用光谱分析和免疫组织化学的方法检测了CD8+T细胞的浸润和效应功能。GCMSCs条件培养液(GCMSC-CM)对胃癌细胞株的作用从蛋白质组、分泌组、免疫印迹和ELISA法等方面进行了研究。在人源化小鼠模型中，GCMSC-CM可减弱PD-1抗体的抗肿瘤活性，抑制免疫应答。在去血清和低氧条件下，GCMSC-CM通过上调PD-L1的表达促进GC细胞的增殖。机制上，GCMSC来源的IL-8和AKT介导的磷酸化促进HK2核定位。磷酸化hk2通过与HIF-1α结合促进PD-L1转录。此外，GCMSC-CM还在体外诱导GC细胞和体内移植瘤中乳酸的过度产生，导致CD8+T细胞的功能受损。此外，CXCR1/2受体耗竭、CXCR2受体拮抗剂AZD5069和IL-8中和抗体的应用也显著逆转了GCMSCs介导的免疫抑制，恢复了PD-1抗体的抗肿瘤能力。结论阻断GCMSCs来源的IL-8/CXCR2途径可减少PD-L1的表达和乳酸的产生，提高抗PD-1免疫治疗的抗肿瘤疗效。
BackgroundAnti-PD-1 immunotherapy has emerged as an important therapeutic modality in advanced gastric cancer (GC). However, drug resistance frequently develops, limiting its effectiveness.MethodsThe role of gastric cancer mesenchymal stem cells (GCMSCs) in anti-PD-1 resistance was evaluated in vivo in NPGCD34+or NCGPBMCxenograft mouse model. In addition, we investigated CD8+T cell infiltration and effector function by spectral cytometry and IHC. The effects of GCMSCs conditional medium (GCMSC-CM) on GC cell lines were characterized at the level of the proteome, secretome using western blot, and ELISA assays.ResultsWe reported that GCMSCs mediated tolerance mechanisms contribute to tumor immunotherapy tolerance. GCMSC-CM attenuated the antitumor activity of PD-1 antibody and inhibited immune response in humanized mouse model. In GC cells under serum deprivation and hypoxia, GCMSC-CM promoted GC cells proliferation via upregulating PD-L1 expression. Mechanistically, GCMSC-derived IL-8 and AKT-mediated phosphorylation facilitated HK2 nuclear localization. Phosphorylated-HK2 promoted PD-L1 transcription by binding to HIF-1α. What is more, GCMSC-CM also induced lactate overproduction in GC cells in vitro and xenograft tumors in vivo, leading to impaired function of CD8+T cells. Furthermore, CXCR1/2 receptor depletion, CXCR2 receptor antagonist AZD5069 and IL-8 neutralizing antibody application also significantly reversed GCMSCs mediated immunosuppression, restoring the antitumor capacity of PD-1 antibody.ConclusionsOur findings reveal that blocking GCMSCs-derived IL-8/CXCR2 pathway decreasing PD-L1 expression and lactate production, improving antitumor efficacy of anti-PD-1 immunotherapy, may be of value for the treatment of advanced gastric carcinoma.Graphical abstract