JAG1 is correlated to suppressive immune microenvironment and predicts immunotherapy resistance in lung adenocarcinoma

Jing He; Lu Li; Lulu Lv; Xiaoyan Chen; Minghui Ge; Yong Ren; Xinyu Tang; Ping Liu; Wen Gao

doi:10.3389/fonc.2023.1091488

JAG1 is correlated to suppressive immune microenvironment and predicts immunotherapy resistance in lung adenocarcinoma

Front Oncol. 2023 Feb 27:13:1091488. doi: 10.3389/fonc.2023.1091488. eCollection 2023.

Authors

Jing He¹, Lu Li^{2

3}, Lulu Lv¹, Xiaoyan Chen^{2

3}, Minghui Ge^{2

3}, Yong Ren^{2

3}, Xinyu Tang⁴, Ping Liu¹, Wen Gao¹

Affiliations

¹ Department of Oncology, Jiangsu Province Hospital and Nanjing Medical University First Affiliated Hospital, Nanjing, China.
² State Key Laboratory of Translational Medicine and Innovative Drug Development, Jiangsu Sincere Diagnostics Co., Ltd., Nanjing, China.
³ Nanjing Sincere Medical Laboratory Science Co., Ltd., Nanjing, China.
⁴ Department of Radiation Oncology, Jiangsu Province Hospital and Nanjing Medical University First Affiliated Hospital, Nanjing, China.

Abstract

Background: 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.

Methods: 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: JAG1, significantly related to prognosis was selected, and further verified by multi-omics data. Finally, we validated that patient with high JAG1 expression had a low immune-infiltrating tumor microenvironment through single-cell transcriptomic data.

Results: 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 JAG1 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 JAG1 may lead to immunosuppressive phenotype due to its strong glycolytic capacity, thus making immunotherapy resistance.

Conclusion: Patients with high expression of JAG1 enhanced glycolytic capacity was likely to cause suppressed immune microenvironment. JAG1 may be a marker for resistance of immunotherapy. Combining anti-angiogenesis therapy could be considered to improve the prognosis of those patients.

Keywords: JAG1; angiogenesis; glycolysis; lung adenocarcinoma; tumor immune microenvironment.

Grants and funding

This work was supported by grants from Natural Science Foundation of Jiangsu Province (BK20210974), National Natural Science Foundation of China (82203148), National Natural Science Foundation of China (82141121), Natural Science Foundation of Jiangsu Province (BK20211380), Jiangsu Province’s Key provincial Talents Program (ZDRCA2016028), The Open Project of Jiangsu Biobank of Clinical Resources (SBK202004003), Beijing XisikeClinical Oncology Research Foundation (Y-MSDPU2021-0223, Y-QL2019-0364), Bethune Young and middle aged Scientific Research training project (BQE-TY-SSPC(2)-N-01), and Scientific research project of Ili Prefecture Clinical Research Institute (yl2020ms11).