Glutaminase inhibition impairs CD8 T cell activation in STK11-/Lkb1-deficient lung cancer
Glutaminase inhibition impairs CD8 T cell activation in STK11-/Lkb1-deficient lung cancer
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DOI：
10.1016/j.cmet.2022.04.003
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发表时间：
2022-06-07
期刊：
影响因子：
29
通讯作者：
Sutherland, Kate D.
中科院分区：
文献类型：
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作者：
Best, Sarah A.;Gubser, Patrick M.;Sutherland, Kate D.
肿瘤微环境（TME）含有丰富的营养来源，可维持细胞生长并促进肿瘤发展。 TME 中的葡萄糖和谷氨酰胺对于发挥抗肿瘤功能的效应 T 细胞的发育和激活至关重要。免疫疗法释放了 T 细胞的抗肿瘤功能，尽管许多实体瘤反应良好，但很大一部分患者并未受益。在 KRAS 突变肺腺癌患者中，KEAP1 和 STK11/Lkb1 共突变与免疫治疗反应受损相关。为了研究 KRAS 突变肺腺癌的代谢和免疫微环境，我们构建了反映这些患者中 KEAP1 和 STK11/Lkb1 突变状况的小鼠模型。在这里，我们发现 Lkb1 缺陷的 TME 中谷氨酸丰度的增加与抗 PD1 反应中 CD8 T 细胞的激活相关。与谷氨酰胺酶抑制剂 CB-839 联合治疗可抑制 CD8 T 细胞的克隆扩增和激活。因此，谷氨酰胺酶抑制会对抗 PD1 免疫疗法激活的 CD8 T 细胞产生负面影响。
The tumor microenvironment (TME) contains a rich source of nutrients that sustains cell growth and facilitate tumor development. Glucose and glutamine in the TME are essential for the development and activation of effector T cells that exert antitumor function. Immunotherapy unleashes T cell antitumor function, and although many solid tumors respond well, a significant proportion of patients do not benefit. In patients with KRAS-mutant lung adenocarcinoma, KEAP1 and STK11/Lkb1 co-mutations are associated with impaired response to immunotherapy. To investigate the metabolic and immune microenvironment of KRAS-mutant lung adenocarcinoma, we generated murine models that reflect the KEAP1 and STK11/Lkb1 mutational landscape in these patients. Here, we show increased glutamate abundance in the Lkb1-deficient TME associated with CD8 T cell activation in response to anti-PD1. Combination treatment with the glutaminase inhibitor CB-839 inhibited clonal expansion and activation of CD8 T cells. Thus, glutaminase inhibition negatively impacts CD8 T cells activated by anti-PD1 immunotherapy.