Division of Rheumatology and Immunology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Program in Cancer Biology, Vanderbilt University, Nashville, Tennessee, USA.
J Clin Invest. 2021 Feb 15;131(4). doi: 10.1172/JCI140100.
Rapidly proliferating tumor and immune cells need metabolic programs that support energy and biomass production. The amino acid glutamine is consumed by effector T cells and glutamine-addicted triple-negative breast cancer (TNBC) cells, suggesting that a metabolic competition for glutamine may exist within the tumor microenvironment, potentially serving as a therapeutic intervention strategy. Here, we report that there is an inverse correlation between glutamine metabolic genes and markers of T cell-mediated cytotoxicity in human basal-like breast cancer (BLBC) patient data sets, with increased glutamine metabolism and decreased T cell cytotoxicity associated with poor survival. We found that tumor cell-specific loss of glutaminase (GLS), a key enzyme for glutamine metabolism, improved antitumor T cell activation in both a spontaneous mouse TNBC model and orthotopic grafts. The glutamine transporter inhibitor V-9302 selectively blocked glutamine uptake by TNBC cells but not CD8+ T cells, driving synthesis of glutathione, a major cellular antioxidant, to improve CD8+ T cell effector function. We propose a "glutamine steal" scenario, in which cancer cells deprive tumor-infiltrating lymphocytes of needed glutamine, thus impairing antitumor immune responses. Therefore, tumor-selective targeting of glutamine metabolism may be a promising therapeutic strategy in TNBC.
快速增殖的肿瘤和免疫细胞需要支持能量和生物量产生的代谢程序。效应 T 细胞和谷氨酰胺成瘾性三阴性乳腺癌 (TNBC) 细胞消耗氨基酸谷氨酰胺，这表明谷氨酰胺可能在肿瘤微环境中存在代谢竞争，可能成为一种治疗干预策略。在这里，我们报告说，在人类基底样乳腺癌 (BLBC) 患者数据集，谷氨酰胺代谢基因与 T 细胞介导的细胞毒性标志物之间存在负相关，谷氨酰胺代谢增加和 T 细胞细胞毒性降低与生存不良相关。我们发现，肿瘤细胞特异性缺失谷氨酰胺酶 (GLS)，一种谷氨酰胺代谢的关键酶，可改善自发的小鼠 TNBC 模型和原位移植中的抗肿瘤 T 细胞激活。谷氨酰胺转运体抑制剂 V-9302 选择性地阻断了 TNBC 细胞但不阻断 CD8+T 细胞对谷氨酰胺的摄取，从而促使合成谷胱甘肽，一种主要的细胞抗氧化剂，以改善 CD8+T 细胞的效应功能。我们提出了一种“谷氨酰胺窃取”的情况，即癌细胞剥夺肿瘤浸润淋巴细胞所需的谷氨酰胺，从而损害抗肿瘤免疫反应。因此，肿瘤选择性靶向谷氨酰胺代谢可能是 TNBC 的一种有前途的治疗策略。
