Inhibition of Glutamine Metabolism Attenuates Tumor Progression Through Remodeling of the Macrophage Immune Microenvironment.

IF 2.6 3区 生物学 Q3 MATERIALS SCIENCE, BIOMATERIALS
Tianhe Li, Sepehr Akhtarkhavari, Sumeng Qi, Jiawei Fan, Tu-Yung Chang, Yao-An Shen, JinMing Yang, Barbara S Slusher, Ie-Ming Shih, Stephanie Gaillard, Tian-Li Wang
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Abstract

Targeting glutamine metabolism has emerged as a promising strategy in cancer therapy. To attain clinical utility, a number of challenges must be overcome, including in vivo anti-tumor activity, pharmacological toxicity, and clinical safety. Aside from glutamine-addicted tumor cells, immune cells may also need glutamine to sustain physiological activities; thus, the current work used two immunological-intact murine cancer models to assess the effects of glutamine antagonists on tumor cells and the immune milieu. To minimize potential off-target effects, we developed a glutamine antagonist prodrug, JHU083, which is bioactivated selectively in cancer tissues. In both murine tumor models, we observed a significant anti-tumor effect, resulting in reduced tumor burden and impeded tumor progression. Single-cell RNA sequencing of tumor tissues demonstrated that JHU083 significantly hampered the immunosuppressive M2-like macrophages but not the pro-inflammatory M1-like macrophages. Expression of Myc- and hypoxia-regulated genes were also inhibited by JHU083. Ex vivo bone marrow-derived macrophage cultures further confirmed that M2 macrophages were more sensitive to glutamine antagonist than M1 macrophages. Together, our findings indicate that JHU083 exerted its anti-tumor activity not only through direct targeting of glutamine-addicted cancer cells but also by shifting the M1/M2 macrophage landscape in favor of an immune-stimulatory microenvironment.

抑制谷氨酰胺代谢通过重塑巨噬细胞免疫微环境减缓肿瘤进展。
靶向谷氨酰胺代谢已成为一种很有前途的癌症治疗策略。为了获得临床应用,必须克服许多挑战,包括体内抗肿瘤活性、药理学毒性和临床安全性。除了谷氨酰胺成瘾的肿瘤细胞外,免疫细胞也可能需要谷氨酰胺来维持生理活动;因此,目前的工作使用两个免疫完整的小鼠癌症模型来评估谷氨酰胺拮抗剂对肿瘤细胞和免疫环境的影响。为了最大限度地减少潜在的脱靶效应,我们开发了一种谷氨酰胺拮抗剂前药JHU083,它在癌症组织中被选择性地生物激活。在两种小鼠肿瘤模型中,我们观察到明显的抗肿瘤作用,从而减轻肿瘤负担,阻碍肿瘤进展。肿瘤组织单细胞RNA测序结果显示,JHU083显著抑制免疫抑制的m2样巨噬细胞,而不抑制促炎的m1样巨噬细胞。JHU083也抑制了Myc-和缺氧调节基因的表达。体外骨髓源性巨噬细胞培养进一步证实M2巨噬细胞比M1巨噬细胞对谷氨酰胺拮抗剂更敏感。总之,我们的研究结果表明,JHU083不仅通过直接靶向谷氨酰胺成瘾的癌细胞,而且通过改变M1/M2巨噬细胞景观,有利于免疫刺激微环境,发挥其抗肿瘤活性。
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
Advanced biology
Advanced biology Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (all)
CiteScore
6.60
自引率
0.00%
发文量
130
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