Comparative profiling of single-cell transcriptome reveals heterogeneity of tumor microenvironment between solid and acinar lung adenocarcinoma

• Published in: Journal of translational medicine 2022-09, Vol.20 (1), p.1-423, Article 423
• Main Authors: Li, Dianke, Yu, Huansha, Hu, Junjie, Li, Shaoling, Yan, Yilv, Li, Shuangyi, Sun, Liangdong, Jiang, Gening, Hou, Likun, Zhang, Lele, Zhang, Peng
• Format: Article
• Language: English
• Subjects: Adenocarcinoma; Cancer therapies; Care and treatment; Chemotherapy; Comparative analysis; Development and progression; Fibroblasts; Fibrosis; Folic acid; Gene expression; Genetic aspects; Genomes; Histology; Hypoxia; Immunotherapy; Kinases; Lung adenocarcinoma; Lung cancer; Lymphocytes T; Mann-Whitney U test; Medical prognosis; Metabolism; Mutation; Myeloid cells; Patients; Phenotypes; Proteomics; Therapeutic targets; Transcriptomes; Transcriptomics; Tumor cells; Tumor immune microenvironment; Tumor metabolism; Tumor microenvironment; Tumors; Ubiquitination
• ISSN: 1479-5876; 1479-5876
• DOI: 10.1186/s12967-022-03620-3

Background The diversity of histologic composition reflects the inter- and intra-tumor heterogeneity of lung adenocarcinomas (LUADs) macroscopically. Insights into the oncological characteristics and tumor microenvironment (TME) of different histologic subtypes of LUAD at the single-cell level can help identify potential therapeutic vulnerabilities and combinational approaches to improve the survival of LUAD patients. Methods Through comparative profiling of cell communities defined by scRNA-seq data, we characterized the TME of LUAD samples of distinct histologic subtypes, with relevant results further confirmed in multiple bulk transcriptomic, proteomic datasets and an independent immunohistochemical validation cohort. Results We find that the hypoxic and acidic situation is the worst in the TME of solid LUADs compared to other histologic subtypes. Besides, the tumor metabolic preferences vary across histologic subtypes and may correspondingly impinge on the metabolism and function of immune cells. Remarkably, tumor cells from solid LUADs upregulate energy and substance metabolic activities, particularly the folate-mediated one-carbon metabolism and the key gene MTHFD2, which could serve as a potential therapeutic target. Additionally, ubiquitination modifications may also be involved in the progression of histologic patterns. Immunologically, solid LUADs are characterized by a predominance of exhausted T cells and immunosuppressive myeloid cells, where the hypoxic, acidified and nutrient-deprived TME has a non-negligible impact. Discrepancies in stromal cell function, evidenced by varying degrees of stromal remodeling and fibrosis, may also contribute to the specific immune phenotype of solid LUADs. Conclusions Overall, our research proposes several potential entry points to improve the immunosuppressive TME of solid LUADs, thereby synergistically potentiating their immunotherapeutic efficacy, and may provide precise therapeutic strategies for LUAD patients of distinct histologic subtype constitution. Keywords: Lung adenocarcinoma, Histology, Tumor immune microenvironment, Tumor metabolism, Immunotherapy