Modulation of oxidative phosphorylation and mitochondrial biogenesis by cigarette smoke influence the response to immune therapy in NSCLC patients. (April 2023)

• Record Type: Journal Article
• Authors: Wang, Yuezhu; Smith, Margaret; Ruiz, Jimmy; Liu, Yin; Kucera, Gregory L.; Topaloglu, Umit; Chan, Michael D.; Li, Wencheng; Su, Jing; Xing, Fei
• Is Part Of: Lung cancer. Volume 178(2023)
• Page Start: 37
• Page End: 46
• Publication Date: 2023-04
• Subjects: NSCLC -- Immune therapy -- Cigarette smoke -- Oxidative phosphorylation; Lungs -- Cancer -- Periodicals; Lung Neoplasms -- Abstracts; Lung Neoplasms -- Periodicals; Poumons -- Cancer -- Périodiques; Lungs -- Cancer; Periodicals; Electronic journals; Electronic journals; 616.99424
• DOI: 10.1016/j.lungcan.2023.01.016
• Languages: English
• ISSNs: 0169-5002

Abstract

Highlights: Oxidative phosphorylation (OXPHOS) and mitochondrial biogenesis are upregulated in NSCLC patients with smoking history. Smoking induced OXPHOS and mitochondrial biogenesis enhance anti-PD-1 efficacy in patients. OPA1 expression is associated with a better response to anti-PD-1 treatment. EGFR mutation is correlated with a decreased response to anti-PD-1 therapy with reduced OXPHOS. All-trans retinoic acid (ATRA) promotes anti-PD-1 efficacy by elevating mitochondrial activity in tumor cells. Abstract: The treatment regimen of non-small cell lung cancer (NSCLC) has drastically changed owing to the superior anti-cancer effects generated by the immune-checkpoint blockade (ICB). However, only a subset of patients experience benefit after receiving ICBs. Therefore, it is of paramount importance to increase the response rate by elucidating the underlying molecular mechanisms and identifying novel therapeutic targets to enhance the efficacy of IBCs in non-responders. We analyzed the progression-free survival (PFS) and overall survival (OS) of 295 NSCLC patients who received anti-PD-1 therapy by segregating them with multiple clinical factors including sex, age, race, smoking history, BMI, tumor grade and subtype. We also identified key signaling pathways and mutations that are enriched in patients with distinct responses to ICB by gene set enrichment analysis (GSEA) and mutational analyses. We found that former and current smokers have a higher response rate to anti-PD-1 treatment than non-smokers. GSEA results revealed that oxidative phosphorylation (OXPHOS) and mitochondrial related pathways are significantly enriched in both responders and smokers, suggesting a potential role of cellular metabolism in regulating immune response to ICB. We also demonstrated that all-trans retinoic acid (ATRA) which enhances mitochondrial function significantly enhanced the efficacy of anti-PD-1 treatment in vivo . Our clinical and bioinformatics based analyses revealed a connection between smoking induced metabolic switch and the response to immunotherapy, which can be the basis for developing novel combination therapies that are beneficial to never smoked NSCLC patients.