Abstract
Lung cancer is the most common cause of cancer deaths worldwide, and lung adenocarcinoma (LUAD) is the most common histological subtype. However, the prognostic and predictive outcomes differ because of this cancer type heterogeneity. LUAD subtypes were identified on the basis of the immunogenomic profiling of 29 immune signatures. We named three LUAD subtypes: Immunity High, Immunity Medium, and Immunity Low. The Immunity High subtype was characterized by immune activation, e.g., increased immune scores, elevated stromal scores and the highest infiltration of CD8+ T cells, and decreased tumor purities. Activated expressions of human leukocyte antigen (HLA) genes, immune checkpoint molecules, and T helper 1 (Th1)/interferon-gamma (IFNγ) gene signature were also observed in the Immunity High subtype. N6-methyladenosine (m6A) RNA methylation, associated with cancer initiation and progression, was reduced in the Immunity High subtype. Functional and signaling pathway enrichment analysis further showed that differentially expressed genes between the Immunity High subtype and the other subtypes mainly participated in immune response and some cancer-associated pathways. In addition, the Immunity High subtype exhibited more sensitivity to immunotherapy and chemotherapy. Finally, candidate compounds that aimed at LUAD subtype differentiation were identified. Comprehensively characterizing the LUAD subtypes based on immune signatures may help to provide potential strategies for LUAD treatment.
Highlights
Lung cancer is the leading cause of cancer-associated mortality worldwide.[1,2] great progress has been made toward the prevention, diagnosis, and treatment of cancer via specific cellular targets, the clinical outcome is still unsatisfactory
The Immunity High Lung adenocarcinoma (LUAD) patients had notably higher proportions of CD8+ T cells (Figure 2E). These results showed that the heterogeneity of immune infiltration in LUAD may comprise targets for immunotherapy and may have significant clinical implications
Functional Annotation and Kyoto Encyclopedia of Genes and Genomes Analyses Here, we found that the Immunity High subtype, compared with Immunity Medium or Immunity Low, was characterized by immune pathway, IFNg pathway, human leukocyte antigen (HLA), and immune checkpoint molecule activation, and inactivation of m6A Messenger RNA (mRNA) demethylation
Summary
Lung cancer is the leading cause of cancer-associated mortality worldwide.[1,2] great progress has been made toward the prevention, diagnosis, and treatment of cancer via specific cellular targets, the clinical outcome is still unsatisfactory. An increasing body of evidence reports that malignant phenotypes are influenced by a tumorrelated microenvironment.[3,4] Lung cancer, an immune-sensitive malignancy, is infiltrated by different immune cell types.[5] Recently, cancer immunotherapy has become involved in treating all forms of cancer and has changed the landscape of cancer care. Lung adenocarcinoma (LUAD) is one of the major types of lung cancer, and a recent study identified an immunogenic tumor microenvironment state in nonsmall cell lung cancer (NSCLC) that was mainly enriched for the LUAD subtype.[10] many studies identified distinct subtypes of LUAD featured by different immune-infiltrating signatures and molecular mechanisms.[11,12] The 5-year overall survival rate of LUAD remains at a low level of 15.9%.13. Many studies identified distinct subtypes of LUAD featured by different immune-infiltrating signatures and molecular mechanisms.[11,12] The 5-year overall survival rate of LUAD remains at a low level of 15.9%.13 it is essential to identify the LUAD subtypes based on immune signature
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