The Peter Doherty Institute for Infection and Immunity and Department of Microbiology and Immunology, University of Melbourne, Parkville, VIC, Australia.
Metabolomics Australia, Bio21 Molecular Science & Biotechnology Institute, University of Melbourne, Parkville, VIC, Australia.
Cell Rep. 2024 Aug 27;43(8):114632. doi: 10.1016/j.celrep.2024.114632. Epub 2024 Aug 18.
Tumor cells undergo uncontrolled proliferation driven by enhanced anabolic metabolism including glycolysis and glutaminolysis. Targeting these pathways to inhibit cancer growth is a strategy for cancer treatment. Critically, however, tumor-responsive T cells share metabolic features with cancer cells, making them susceptible to these treatments as well. Here, we assess the impact on anti-tumor T cell immunity and T cell exhaustion by genetic ablation of lactate dehydrogenase A (LDHA) and glutaminase1 (GLS1), key enzymes in aerobic glycolysis and glutaminolysis. Loss of LDHA severely impairs expansion of T cells in response to tumors and chronic infection. In contrast, T cells lacking GLS1 can compensate for impaired glutaminolysis by engaging alternative pathways, including upregulation of asparagine synthetase, and thus efficiently respond to tumor challenge and chronic infection as well as immune checkpoint blockade. Targeting GLS1-dependent glutaminolysis, but not aerobic glycolysis, may therefore be a successful strategy in cancer treatment, particularly in combination with immunotherapy.
肿瘤细胞经历不受控制的增殖，这是由增强的合成代谢代谢驱动的，包括糖酵解和谷氨酰胺分解。针对这些途径抑制癌症生长是癌症治疗的一种策略。然而，至关重要的是，肿瘤反应性 T 细胞与癌细胞具有代谢特征，使它们也容易受到这些治疗的影响。在这里，我们通过基因敲除乳酸脱氢酶 A (LDHA) 和谷氨酰胺酶 1 (GLS1) 来评估对抗肿瘤 T 细胞免疫和 T 细胞耗竭的影响，这两种酶是有氧糖酵解和谷氨酰胺分解的关键酶。LDHA 的缺失严重损害了 T 细胞对肿瘤和慢性感染的反应性扩张。相比之下，缺乏 GLS1 的 T 细胞可以通过参与替代途径（包括天冬酰胺合成酶的上调）来补偿谷氨酰胺分解的受损，因此能够有效地对肿瘤挑战和慢性感染以及免疫检查点阻断做出反应。因此，靶向 GLS1 依赖性谷氨酰胺分解，而不是有氧糖酵解，可能是癌症治疗的一种成功策略，特别是与免疫疗法联合使用时。
