Targeting glutamine metabolism enhances tumor-specific immunity by modulating suppressive myeloid cells
Targeting glutamine metabolism enhances tumor-specific immunity by modulating suppressive myeloid cells
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DOI：
10.1172/jci131859
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发表时间：
2020-07-01
影响因子：
15.9
通讯作者：
Powell, Jonathan D.
中科院分区：
文献类型：
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作者：
Oh, Min-Hee;Sun, Im-Hong;Powell, Jonathan D.
骨髓细胞是肿瘤微环境（TME）的主要组成部分，它促进肿瘤生长和免疫逃避。通过使用谷氨酰胺代谢的小分子抑制剂，我们不仅能够抑制肿瘤生长。但我们显著抑制了骨髓源性抑制细胞（MDSC）的产生和募集。靶向肿瘤谷氨酰胺代谢导致CSF3减少，从而导致MDSC募集以及免疫原性细胞死亡，导致炎性肿瘤相关巨噬细胞（TAM）增加。或者，抑制MDSC自身的谷氨酰胺代谢导致活化诱导的细胞死亡和MDSC向炎性巨噬细胞的转化。令人惊讶的是，阻断谷氨酰胺代谢也抑制肿瘤和骨髓来源的细胞的IDO表达，导致犬尿氨酸水平显著降低。这反过来又抑制了转移的发展，并进一步增强了抗肿瘤免疫力。事实上，靶向谷氨酰胺代谢使检查点阻断抗性肿瘤对免疫疗法敏感。总的来说，我们的研究确定了肿瘤的独特代谢和抑制性免疫细胞的代谢之间的密切相互作用。
Myeloid cells comprise a major component of the tumor microenvironment (TME) that promotes tumor growth and immune evasion. By employing a small-molecule inhibitor of glutamine metabolism, not only were we able to inhibit tumor growth. but we markedly inhibited the generation and recruitment of myeloid-derived suppressor cells (MDSCs). Targeting tumor glutamine metabolism led to a decrease in CSF3 and hence recruitment of MDSCs as well as immunogenic cell death, leading to an increase in inflammatorytumor-associated macrophages (TAMs). Alternatively, inhibiting glutamine metabolism of the MDSCs themselves led to activation-induced cell death and conversion of MDSCs to inflammatory macrophages. Surprisingly, blocking glutamine metabolism also inhibited IDO expression of both the tumor and myeloid-derived cells, leading to a marked decrease in kynurenine levels. This in turn inhibited the development of metastasis and further enhanced antitumor immunity. Indeed, targeting glutamine metabolism rendered checkpoint blockade-resistant tumors susceptible to immunotherapy. Overall, our studies define an intimate interplay between the unique metabolism of tumors and the metabolism of suppressive immune cells.