School of Medicine, Jiangsu University, 301 Xuefu Road, Jingkou District, Zhenjiang, Jiangsu, China.
Department of Clinical Laboratory, Affiliated Hospital of Jining Medical University, Jining, Shandong, China.
Gastric Cancer. 2023 Sep;26(5):691-707. doi: 10.1007/s10120-023-01405-1. Epub 2023 Jun 10.
Anti-PD-1 immunotherapy has emerged as an important therapeutic modality in advanced gastric cancer (GC). However, drug resistance frequently develops, limiting its effectiveness.
The role of gastric cancer mesenchymal stem cells (GCMSCs) in anti-PD-1 resistance was evaluated in vivo in NPG or NCG xenograft mouse model. In addition, we investigated CD8T 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.
We 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.
Our 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.
抗 PD-1 免疫疗法已成为晚期胃癌（GC）的重要治疗方法。然而，药物耐药性经常发生，限制了其疗效。
我们在 NPG 或 NCG 异种移植小鼠模型中评估了胃癌间质干细胞（GCMSCs）在抗 PD-1 耐药中的作用。此外，我们通过光谱细胞术和 IHC 研究了 CD8T 细胞浸润和效应功能。使用 Western blot 和 ELISA 测定法，在蛋白质组和分泌组水平上研究了 GCMSC 条件培养基（GCMSC-CM）对 GC 细胞系的影响。
我们报道了 GCMSCs 介导的耐受机制有助于肿瘤免疫治疗耐受。GCMSC-CM 减弱了 PD-1 抗体的抗肿瘤活性并抑制了人源化小鼠模型中的免疫反应。在血清剥夺和缺氧下的 GC 细胞中，GCMSC-CM 通过上调 PD-L1 表达促进 GC 细胞增殖。从机制上讲，GCMSC 衍生的 IL-8 和 AKT 介导的磷酸化促进了 HK2 的核定位。磷酸化-HK2 通过与 HIF-1α 结合促进 PD-L1 转录。更重要的是，GCMSC-CM 还在体外 GC 细胞和体内异种移植肿瘤中诱导乳酸过度产生，导致 CD8 T 细胞功能受损。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 介导的免疫抑制作用，恢复了 PD-1 抗体的抗肿瘤能力。
我们的研究结果表明，阻断 GCMSCs 衍生的 IL-8/CXCR2 通路降低 PD-L1 表达和乳酸产生，可提高抗 PD-1 免疫治疗的抗肿瘤疗效，可能对晚期胃癌的治疗有价值。
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