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Integrating bulk-RNA sequencing and single-cell sequencing analyses to characterize adenosine-enriched tumor microenvironment landscape and develop an adenosine-related prognostic signature predicting immunotherapy in lung adenocarcinoma

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Abstract

The adenosine-signaling axis has been recognized as an important immunomodulatory pathway in tumor immunity. However, the biological role of the adenosine-signaling axis in the remodeling of the tumor microenvironment (TME) in lung adenocarcinoma (LUAD) remains unclear. Here, we quantified adenosine signaling (ado_sig) in LUAD samples using the GSVA method and assessed the prognostic value of adenosine in LUAD. Afterward, we explored the heterogeneity of the tumor-immune microenvironment at different adenosine levels. In addition, we analyzed the potential biological pathways engaged by adenosine. Next, we established single-cell transcriptional profiles of LUAD and analyzed cellular composition and cell-cell communication analysis under different adenosine microenvironments. Moreover, we established adenosine-related prognostic signatures (ARS) based on comprehensive bioinformatics analysis and evaluated the efficacy of ARS in predicting immunotherapy. The results demonstrated that adenosine signaling adversely impacted the survival of immune-enriched LUAD. The high-adenosine microenvironment exhibited elevated pro-tumor-immune infiltration, including M2 macrophages and displayed notably increased epithelial-mesenchymal transition (EMT) transformation. Furthermore, adenosine signaling displayed significant associations with the expression patterns and prognostic value of immunomodulators within the TME. Single-cell sequencing data revealed increased fibroblast occupancy and a prominent activation of the SPP1 signaling pathway in the high adenosine-signaling microenvironment. The ARS exhibited promising effectiveness in prognostication and predicting immunotherapy response in LUAD. In summary, overexpression of adenosine can cause a worsened prognosis in the LUAD with abundant immune infiltration. Moreover, increased adenosine levels are associated with pro-tumor-immune infiltration, active EMT transformation, pro-tumor angiogenesis, and other factors promoting cancer progression, which collectively contribute to the formation of an immunosuppressive microenvironment. Importantly, the ARS developed in this study demonstrate high efficacy in evaluating the response to immunotherapy.

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The original contributions presented in the study are included in the article/supplementary material; further inquiries can be directed to the corresponding authors.

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Acknowledgements

We are grateful to the patients and staff who participated in GEO and TCGA.

Funding

This study was sponsored by the National Natural Science Foundation of China (81971483); the Collaborative Innovation Project of Colleges and Universities of Anhui Province (GXXT-2020-058); Anhui Province Engineering Laboratory of Occupational Health and Safety (AYZJSGCLK202201001, AYZJSGCLK202201002, AYZJSGCLK 202202001); Key Laboratory of Industrial Dust Deep Reduction and Occupational Health and Safety of Anhui Higher Education Institutes (AYZJSGXLK202202002); the Innovation and Entrepreneurship Project of Anhui University of Science and Technology (2021CX2125, 2021CX2126, 2021CX2124); and Scientific Research Foundation for High-level Talents of Anhui University of Science and Technology (2022y jrc14).

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  1. School of Medicine, Anhui University of Science and Technology, Chongren Building, No 168, Taifeng St, Huainan, People’s Republic of China

    Tao Han, Jing Wu, Yafeng Liu, Jiawei Zhou, Rui Miao, Jianqiang Guo, Zhi Xu, Yingru Xing, Ying Bai & Dong Hu

  2. Anhui Province Engineering Laboratory of Occupational Health and Safety, Anhui University of Science and Technology, Huainan, People’s Republic of China

    Tao Han, Jing Wu, Yafeng Liu, Jiawei Zhou, Jianqiang Guo, Ying Bai & Dong Hu

  3. Department of Clinical Laboratory, Anhui Zhongke Gengjiu Hospital, Hefei, People’s Republic of China

    Yingru Xing

  4. Key Laboratory of Industrial Dust Prevention and Control & Occupational Safety and Health of the Ministry of Education, Anhui University of Science and Technology, Huainan, People’s Republic of China

    Dong Hu

  5. Department of Laboratory Medicine, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, People’s Republic of China

    Dong Hu

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Contributions

HD, BY, and WJ: conception and design this manuscript. HT prepared the original data and drafted the manuscript. XYR, ZJW, and GJQ: development of methodology, analysis and interpretation of data, and writing of the manuscript. MR, XZ, and LY: review of the manuscript.

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Correspondence to Tao Han, Ying Bai or Dong Hu.

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Han, T., Wu, J., Liu, Y. et al. Integrating bulk-RNA sequencing and single-cell sequencing analyses to characterize adenosine-enriched tumor microenvironment landscape and develop an adenosine-related prognostic signature predicting immunotherapy in lung adenocarcinoma. Funct Integr Genomics 24, 19 (2024). https://doi.org/10.1007/s10142-023-01281-z

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