Comprehensive Exploration of M2 Macrophages and Its Related Genes for Predicting Clinical Outcomes and Drug Sensitivity in Lung Squamous Cell Carcinoma.

Background: M2 macrophages play an important role in cancers. However, the role of M2 macrophages has not been clarified in lung squamous cell carcinoma.

Methods: All the open-accessed data were downloaded from The Cancer Genome Atlas database. All the analysis was performed in the R software. The CIBERSORT algorithm was utilized to quantify the immune cell infiltration in the tumor microenvironment. LASSO regression and multivariate Cox regression analysis were carried out for the creation of the prognostic model. Pathway enrichment analysis was performed using the single sample Gene Set Enrichment Analysis (ssGSEA) and clueGO algorithm.

Results: In our study, we comprehensively explored the role of M2 macrophages and its related genes in LUSC patients. We found that the patients with high M2 macrophage infiltration tend to have a worse prognosis. Also, some oncogenetic pathways were activated in the patients with high M2 macrophage infiltration. Further, a prognosis model based on six M2 macrophage-related genes was established, including TRIM58, VIPR2, CTNNA3, KIAA0408, CLEC4G, and MATN4, which showed a good prognosis prediction efficiency in both training and validation cohort. Pathway enrichment analysis showed that the pathway of allograft rejection, bile acid metabolism, coagulation, inflammatory response, IL6/JAK/STAT3 signaling, hedgehog signaling, peroxisome, and myogenesis were significantly activated in the high-risk patients. Based on the results of an investigation of immune infiltration, risk score was found to have a positive correlation with M2 macrophages and resting CD4+ memory T cells, but a negative correlation with follicular helper T cells, M1 macrophages, and Tregs. In addition, we discovered that patients in high-risk groups may respond better to immunotherapy than individuals in lower-risk groups. However, low-risk patients might be more sensitive to cisplatin.

Conclusions: Our model is a powerful tool to predict LUSC patient prognosis and could indicate the sensitivity of immunotherapy and chemotherapy.