Abstract 1980: Cigarette smoke induced oxidative phosphorylation and mitochondrial biogenesis enhance response to immune therapy in NSCLC patients
Authors: Wang Yuezhu , Ruiz Jimmy , Liu Yin , Smith Margaret , Kucera Gregory , Topaloglu Umit , Chan Michael , O’Neill Stacey , Su Jing , Xing Fei 
Published: June 2022

Abstract
Background: 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. There are several treatments including combination of PD-1 blockade and low dose chemotherapy, but only few robust synergetic effects were reported. 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.
Methods: 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. Tumor samples from 48 patients were sequenced and their genomic profiles were extracted for analyses. We identified key signaling pathways and mutations that are enriched in those patients with distinct responses to ICB by gene set enrichment analysis (GSEA) and mutational analyses. The efficacy of combination treatment with mitochondrial activator, all-trans retinoic acid (ATRA) and PD-1 antibody is evaluated in LL/2 and CMT167 murine lung cancer model.
Results: We found that smoking status was the only parameter that was correlated with the ICB responses compared to sex, age, race, BMI, tumor grade and subtype. 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 ATRA which increased mitochondrial function significantly by MitoSox and MitoTrack 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.
Conclusion: In this study, we discovered that smokers respond better to immune therapy than non-smokers due to elevated OXPHOS capacity and mitochondrial activity, which could be a potential target to boost the response to immune therapy in NSCLC patients who never smoked.
Citation Format: Yuezhu Wang, Jimmy Ruiz, Yin Liu, Margaret Smith, Gregory Kucera, Umit Topaloglu, Michael Chan, Stacey O’Neill, Jing Su, Fei Xing. Cigarette smoke induced oxidative phosphorylation and mitochondrial biogenesis enhance response to immune therapy in NSCLC patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1980.