Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, China; Department of Radiation Oncology and Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences Jinan, Shandong, China; Research Unit of Radiation Oncology, Chinese Academy of Medical Sciences, Jinan, Shandong, China.
Department of Radiation Oncology and Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences Jinan, Shandong, China; Research Unit of Radiation Oncology, Chinese Academy of Medical Sciences, Jinan, Shandong, China.
Comput Biol Med. 2023 Oct;165:107415. doi: 10.1016/j.compbiomed.2023.107415. Epub 2023 Aug 29.
In recent years, targeting glutamine metabolism has gained attention as a promising therapeutic approach. Glutamine catabolic-related enzymes play a crucial role in modulating glutamine metabolism and influencing immune responses in the tumor immune microenvironment (TME). However, current literature on the function of glutamine catabolic enzymes in lung adenocarcinoma (LUAD) is limited.
We validated the glutamine dependency of LUAD cells in vitro, followed by transcriptome data to identify differentially expressed genes (DEGs), with transcriptome and single-cell data analysis utilized to explore the role of such genes within the tumor immune microenvironment. We performed employed subcutaneous injection of lewis lung carcinoma cells in C57BL/6 mice to confirm the role of candidate genes in tumor growth and anti-tumor immunity.
Our study revealed that glutamine is essential for the growth of LUAD cells. Subsequently, we identified four DEGs - glutamate pyruvate transaminase 1 (GPT1), glutamate pyruvate transaminase 2 (GPT2), glutamic-oxaloacetic transaminase 1 (GOT1), and glutamic-oxaloacetic transaminase 2 (GOT2) - in LUAD patients, which were highly expressed in tumor tissue and associated with an immunosuppressive TME. Single-cell sequencing analysis detected high expression levels of GOT1 and GOT2 in immune and stromal cell subpopulations, while GPT1 and GPT2 showed relatively lower expression. Based on the lower immune score and lower expression in immune and stromal cells, we validated the role of GPT2 in vivo for modulating the TME and tumor growth. Inhibition of GPT2 resulted in suppressed tumor growth and increased the expression of CD4 and CD8. Additionally, GPT2 inhibitors induced a stronger antitumor immunity when used in combination with anti-programmed cell death ligand 1.
This study is the first to show the critical role of glutamine catabolic-related enzymes in the TME, and identified GPT2 as a promising therapeutic target for inhibiting tumor growth and improving anti-tumour immune responses for LUAD. Additional studies will be required to define the roles glutamine catabolic-related enzymes play in LUAD.
近年来，靶向谷氨酰胺代谢已成为一种很有前途的治疗方法。谷氨酰胺分解代谢相关酶在调节谷氨酰胺代谢和影响肿瘤免疫微环境（TME）中的免疫反应方面起着至关重要的作用。然而，目前关于谷氨酰胺分解代谢酶在肺腺癌（LUAD）中的作用的文献有限。
我们在体外验证了 LUAD 细胞对谷氨酰胺的依赖性，然后通过转录组数据鉴定差异表达基因（DEGs），并利用转录组和单细胞数据分析来探索这些基因在肿瘤免疫微环境中的作用。我们通过在 C57BL/6 小鼠中皮下注射 Lewis 肺癌细胞来验证候选基因在肿瘤生长和抗肿瘤免疫中的作用。
我们的研究表明，谷氨酰胺是 LUAD 细胞生长所必需的。随后，我们在 LUAD 患者中鉴定出四个 DEGs——谷氨酸丙酮酸转氨酶 1（GPT1）、谷氨酸丙酮酸转氨酶 2（GPT2）、谷草转氨酶 1（GOT1）和谷草转氨酶 2（GOT2），这些基因在肿瘤组织中高表达，并与免疫抑制性 TME 相关。单细胞测序分析检测到 GOT1 和 GOT2 在免疫和基质细胞亚群中高表达，而 GPT1 和 GPT2 表达相对较低。基于较低的免疫评分和免疫细胞和基质细胞中的低表达，我们在体内验证了 GPT2 调节 TME 和肿瘤生长的作用。抑制 GPT2 导致肿瘤生长受到抑制，并增加了 CD4 和 CD8 的表达。此外，当与抗程序性细胞死亡配体 1 联合使用时，GPT2 抑制剂诱导了更强的抗肿瘤免疫。
本研究首次表明谷氨酰胺分解代谢相关酶在 TME 中起着关键作用，并确定 GPT2 是抑制 LUAD 肿瘤生长和改善抗肿瘤免疫反应的有前途的治疗靶点。需要进一步的研究来确定谷氨酰胺分解代谢相关酶在 LUAD 中的作用。
