He Jing, Li Lu, Lv Lulu, Chen Xiaoyan, Ge Minghui, Ren Yong, Tang Xinyu, Liu Ping, Gao Wen
Department of Oncology, Jiangsu Province Hospital and Nanjing Medical University First Affiliated Hospital, Nanjing, China.
State Key Laboratory of Translational Medicine and Innovative Drug Development, Jiangsu Sincere Diagnostics Co., Ltd., Nanjing, China.
Front Oncol. 2023 Feb 27;13:1091488. doi: 10.3389/fonc.2023.1091488. eCollection 2023.
The current exploration of the tumor immune microenvironment is enthusiastic, but few studies explored the impact of angiogenesis on the immune microenvironment. Immunotherapy combined with anti-angiogenesis therapy has become one of the first-line treatment for lung adenocarcinoma. Our study aimed to explore the reasons for resistance of immunotherapy, and explore markers for immunotherapy combined with anti-angiogenesis therapy.
First, by unsupervised clustering of 36 angiogenesis-related genes in lung adenocarcinoma patients from TCGA database, AGS1 and AGS2 groups were distinguished with significantly different clinical outcomes. Secondly, the immune microenvironment and metabolic characteristics were analyzed. Next, we used the GDSC and GEO database to analyze therapeutic responses. Then, through multivariate Cox regression, the hub gene: , significantly related to prognosis was selected, and further verified by multi-omics data. Finally, we validated that patient with high expression had a low immune-infiltrating tumor microenvironment through single-cell transcriptomic data.
Compared with the AGS1 group, AGS2 showed an immune "cold" phenotype with lower lymphocyte infiltration, and was associated with worse prognoses. At the same time, the immunosuppressive TGF-β response was significantly higher in AGS2. Furthermore, the glycolysis ability of the AGS2 was stronger than AGS1. The expression of was significantly higher in the AGS2, and was significantly negatively correlated with the degree of immune infiltration, accompanying with higher glycolytic capacity. The above results indicate that patients with high expression of may lead to immunosuppressive phenotype due to its strong glycolytic capacity, thus making immunotherapy resistance.
Patients with high expression of enhanced glycolytic capacity was likely to cause suppressed immune microenvironment. may be a marker for resistance of immunotherapy. Combining anti-angiogenesis therapy could be considered to improve the prognosis of those patients.
目前对肿瘤免疫微环境的探索热情高涨，但很少有研究探讨血管生成对免疫微环境的影响。免疫疗法联合抗血管生成疗法已成为肺腺癌的一线治疗方法之一。我们的研究旨在探讨免疫疗法耐药的原因，并探索免疫疗法联合抗血管生成疗法的标志物。
首先，通过对TCGA数据库中肺腺癌患者的36个血管生成相关基因进行无监督聚类，区分出临床结局显著不同的AGS1和AGS2组。其次，分析免疫微环境和代谢特征。接下来，我们使用GDSC和GEO数据库分析治疗反应。然后，通过多变量Cox回归，选择与预后显著相关的枢纽基因： ，并通过多组学数据进一步验证。最后，我们通过单细胞转录组数据验证了高表达 的患者具有低免疫浸润的肿瘤微环境。
与AGS1组相比，AGS2表现出免疫“冷”表型，淋巴细胞浸润较低，且与较差的预后相关。同时，AGS2中免疫抑制性TGF-β反应显著更高。此外，AGS2组的糖酵解能力比AGS1组更强。 在AGS2中的表达显著更高，且与免疫浸润程度显著负相关，同时具有更高的糖酵解能力。上述结果表明，高表达 的患者可能因其强大的糖酵解能力导致免疫抑制表型，从而产生免疫疗法耐药性。
高表达 且糖酵解能力增强的患者可能导致免疫微环境受到抑制。 可能是免疫疗法耐药的标志物。可以考虑联合抗血管生成疗法来改善这些患者的预后。
