Multidimensional characterization of the tumor microenvironment profiles in lung squamous cell carcinoma

Tumor microenvironment (TME) plays an important role in tumorigenesis, development, metastasis, and drug sensitivity, but little is known about it in lung squamous cell carcinoma (LUSC). Here, the RNA-sequencing data, clinical and survival data of patients with LUSC in The Cancer Genome Atlas, and six independent datasets were collected. Based on the unsupervised clustering of knowledge-based functional gene expression signatures, LUSC was classified into four subtypes. Cluster 1 and cluster 3 exhibited substantial tumor immune infiltration, suggesting a better response to immunotherapy. Relatively worse survival was observed in cluster 4, probably due to higher angiogenesis. Besides, differentially expressed genes in cluster 1, cluster 2, and cluster 3 were prominently enriched in immune-related pathways, whereas extracellular matrix-related pathways were enriched for cluster 4. Genomic data analyses showed significant variations in tumor mutational burden and mutational frequency of several genes, such as tumor protein P53 (TP53), among the four subtypes. In addition, the four subtypes exhibited heterogeneity in the sensitivity of commonly used chemotherapy drugs for lung cancer and the intratumor microbiome profile. Finally, a prognostic model was developed, and its performance and generalization ability were independently validated in multiple datasets. Overall, our study advances the understanding of the TME in LUSC and proposes a prognostic model that facilitates clinical decision-making.NEW & NOTEWORTHY This study obtained four immunological subtypes exhibiting substantial difference in the tumor microenvironment (TME), immune-related pathways, tumor mutational burden, drug sensitivity, and intratumor microbiome. Furthermore, we developed a novel prognostic model consisting of 11 signature genes showing excellent performance in predicting prognosis. Our study deepens the understanding of the heterogeneity of the TME in lung squamous cell carcinoma (LUSC) and contributes to the precision therapy of patients with LUSC.