Methionine restriction promotes the polarization of macrophages towards M1 and the immunotherapy effect of PD-L1/PD-1 blockades by inhibiting the secretion of MIF by gastric carcinoma cells

IF 5 2区医学 Q2 Medicine

Translational Oncology Pub Date : 2024-11-13 DOI:10.1016/j.tranon.2024.102181

Lin Xin , Jiang Liu , Jun-Yan Lai , He-Song Xu , Luo-Jun Fan , Yong-Hui Zou , Qi Zhou , Zhen- Qi Yue , Jin-Heng Gan

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引用次数: 0

Abstract

Background

The limited curative effect of PD-L1/PD-1 blockades presents challenges to immunotherapy for advanced gastric cancer. We have found that methionine restriction (MR) enhances the drug resistance of gastric carcinoma cells. We aimed to explore whether MR can enhance the efficacy of PD-L1/PD-1 blockades in gastric cancer.

Methods

To conduct MR, gastric carcinoma cells were transfected with LV-METase in vitro, and 615 mice were injected with MFC cells with stable METase expression in vivo. Flow cytometry was conducted to measure the proportions of M1/M2 macrophages and CD8⁺ GZMB⁺/IFN-γ⁺ T cells. Additionally, the levels of M1/M2 macrophage markers and MIF were also detected.

Results

MR increased M1 and down-regulated M2 macrophages. MR suppressed MIF levels in gastric carcinoma cells, while the addition of anti-MIF neutralizing antibody inhibited the effect of MR on macrophage M1/M2 polarization. MR enhanced the increase of the proportion of CD8⁺ GZMB⁺ T cells and CD8⁺ IFN-γ⁺ T cells induced by PD-L1/PD-1 blockades. In vivo detection verified the efficacy of the combination of MR and PD-L1/PD-1 blockades on gastric cancer.

Conclusions

MR inhibits the secretion of MIF by gastric carcinoma cells, promotes macrophage M1 polarization, and enhances the therapeutic effect of PD-L1/PD-1 blockades in gastric cancer.

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通过抑制胃癌细胞分泌 MIF，限制蛋氨酸可促进巨噬细胞向 M1 分化，并促进 PD-L1/PD-1 阻断剂的免疫治疗效果。

背景：PD-L1/PD-1阻断剂的疗效有限，这给晚期胃癌的免疫疗法带来了挑战。我们发现蛋氨酸限制（MR）会增强胃癌细胞的耐药性。我们的目的是探讨 MR 能否增强 PD-L1/PD-1 阻断剂在胃癌中的疗效：为了进行MR研究，我们在体外用LV-METase转染了胃癌细胞，并在体内给615只小鼠注射了稳定表达METase的MFC细胞。流式细胞术测量了 M1/M2 巨噬细胞和 CD8+ GZMB+/IFN-γ+ T 细胞的比例。此外，还检测了 M1/M2 巨噬细胞标记物和 MIF 的水平：结果：MR增加了M1巨噬细胞，下调了M2巨噬细胞。MR抑制了胃癌细胞中的MIF水平，而加入抗MIF中和抗体则抑制了MR对巨噬细胞M1/M2极化的影响。MR增强了PD-L1/PD-1阻断剂诱导的CD8+ GZMB+ T细胞和CD8+ IFN-γ+ T细胞比例的增加。体内检测验证了MR和PD-L1/PD-1阻断剂联合使用对胃癌的疗效：结论：MR能抑制胃癌细胞分泌MIF，促进巨噬细胞M1极化，增强PD-L1/PD-1阻断剂对胃癌的治疗效果。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Translational Oncology ONCOLOGY-

CiteScore

8.40

自引率

2.00%

发文量

314

审稿时长

54 days

期刊介绍： Translational Oncology publishes the results of novel research investigations which bridge the laboratory and clinical settings including risk assessment, cellular and molecular characterization, prevention, detection, diagnosis and treatment of human cancers with the overall goal of improving the clinical care of oncology patients. Translational Oncology will publish laboratory studies of novel therapeutic interventions as well as clinical trials which evaluate new treatment paradigms for cancer. Peer reviewed manuscript types include Original Reports, Reviews and Editorials.