Comprehensive analysis of the immunogenic cell death-related signature for predicting prognosis and immunotherapy efficiency in patients with lung adenocarcinoma

Abstract

Abstract Background Although immunotherapy has been considered as a potent strategy for lung adenocarcinoma (LUAD), only a small part of patients was served as potentially clinical benefiters. Immunogenic cell death (ICD), a type of regulated cell death (RCD), which enable to reshape the tumor immune microenvironment and contribute to the immunotherapy efficiency. Developing a novel ICD-based signature may be a potential strategy to differentiate prognosis of patients with LUAD and predict efficacy of immunotherapy. Methods In this study, 34 ICD-related genes (ICDRGs) were identified and analyzed in LUAD samples from the Cancer Genome Atlas (TCGA). 572 patients with LUAD were divided into two distinct clusters according to ICDRGs expression levels. Patients were subsequently classified into two distinct gene subtypes based on differentially expressed genes (DEGs) analyzed between two ICD-related clusters. We further developed and validated a novel ICD-related score (ICDRS) followed by comprehensive investigation about the landscape of the prognosis, immune-based features, immunotherapautic responses and sensitivity of target drugs in patients with LUAD. Results After confirming transcriptomic aberrations and appraising prognostic value of ICDRGs, two ICD-associated subtypes were initially determined by consensus clustering in accordance with differentially expressional levels of ICDRGs. It was shown that patients in the ICD high-subtype possessed the superior clinical prognosis, abundant immune cell infiltration and higher involvement in immune-related signaling compared with the ICD low-subtype. A signature of ICD-related score (ICDRS) was further established and validated, which was served as an independent prognostic indicator for LUAD patients. These comprehensive results revealed that the high-score patients represented better clinical prognosis, higher immune infiltration-related characteristics, stronger expression of immune checkpoints, and better response to immune checkpoint inhibitor therapy and multiple targeted drugs. To further verify our analysis, we selected TLR4 as the representative of ICDRGs and evaluated its expression on the lung normal cells and cancer cells in vitro. Then, relative animal experiments were performed in vivo, with results of that the stimulation of TLR4 suppressed the growth of lung cancer. Conclusions In conclusion, our comprehensive analysis of ICDRGs in LUAD demonstrated their function in serving as a biomarker of predicting prognosis and clinical effects of immunotherapy and targeted drugs, which is meaningful to improve our understanding of ICDRGs and brought inspirations about evaluating prognosis and developing effective therapeutic strategies to patients with LUAD.

Keywords

• Lung adenocarcinoma
• Immunogenic cell death
• Tumor microenvironment
• Immunotherapy efficacy
• Prognosis