An immune indicator based on BTK and DPEP2 identifies hot and cold tumors and clinical treatment outcomes in lung adenocarcinoma.

In lung adenocarcinoma (LUAD), immune heterogeneity of hot and cold tumors has been recognized as one of the major factors affecting immunotherapy and other common treatments. However, there is still a lack of biomarkers that can effectively identify the immunophenotype of cold and hot tumors. First, the immune signatures were obtained based on literature mining, including macrophage/monocyte, IFN-γ response, TGF-β response, IL12 response, lymphocyte activation, and ECM/Dve/immune response. Subsequently, LUAD patients were further clustered into different immune phenotypes based on these immune signatures. Next, the key genes related to the immune phenotypes were screened by WGCNA analysis, univariate analysis, and lasso-cox analysis, and the risk signature was established via the key genes. In additional, we compared the clinicopathological characteristics, drug sensitivity, the abundance of immune infiltration, and the efficacy of immunotherapy and commonly used therapies between patients in the high- and low-risk groups in LUAD. LUAD patients were divided into immune hot phenotype and immune cold phenotype groups. The clinical presentation showed that patients with the immune hot phenotype had higher immunoactivity (including higher MHC, CYT, immune, stromal, ESTIMATE scores, higher abundance of immune cell infiltration, higher abundance of TIL, and enrichment of immune-enriched subtypes) and better survival outcomes than those with the immune cold phenotype. Subsequently, WGCNA analysis, univariate analysis, and lasso-cox analysis identified the genes highly associated with the immune phenotype: BTK and DPEP2. The risk signature, consisting of BTK and DPEP2, is highly correlated with the immune phenotype. High-risk scores were enriched in patients with immune cold phenotype and low-risk scores were enriched in patients with immune hot phenotype. Compared to the high-risk group, the low-risk group had better clinical performance, higher drug sensitivity, and a higher degree of immunoactivity, as well as better efficacy in receiving immunotherapy and common adjuvant therapy. This study developed an immune indicator consisting of BTK and DPEP2 based on the heterogeneity of hot and cold Immunophenotypes of the tumor microenvironment. This indicator has good efficacy in predicting prognosis and assessing the efficacy of immunotherapy, chemotherapy, and radiotherapy. It has the potential to facilitate personalized and precise treatment of LUAD in the future.