Abstract 649: Comparative effects of combustible cigarette versus electronic cigarette exposures on K-ras mutant lung cancer

Abstract Combustible cigarette smoking (CCS) is causally related to ~90% of all lung cancers and induces various tumor-initiating effects, some of which (e.g., inflammation) are not reversible even after smoking cessation. More recently, use of non-combustible smoking vectors, such as electronic cigarette vapors (ECV), have rapidly increased, especially among youth. Despite this emerging public health concern, the long-term impact of ECV exposure is poorly understood. Our lab sought to assess the safety of ECV and determine their influence on immune dysfunction and lung cancer progression by comparing the effects of CCS and ECV in an airway epithelial specific K-ras mutant mouse model of lung adenocarcinoma (CC-LR). Three cohorts of 6-week-old CC-LR mice were exposed to either room air, CCS, or ECV 5 days per week for 8 weeks. For CCS exposure, mice were exposed to CCS from 3R4F research cigarettes at a rate of 3 puffs/min for 2 hours each day using the SCIREQ integrated Cigarette Smoking Robot. For ECV exposure, mice were exposed to 72 mg/ml of liquid nicotine in 50% propylene glycol/vegetable glycerin solution at a rate of 3 puffs/min for 2 hours using the SCIREQ Electronic Nicotine Delivery System. While CCS led to a significant increase in tumor burden (25%), ECV showed no significant changes compared to room air-exposed control. Bronchoalveolar lavage fluid had significantly increased total lung immune cell infiltrates in both CCS (30%) and ECV (25%), particularly in macrophage and lymphocyte populations. Immunophenotyping of CCS and ECV exposed lungs displayed pronounced pro-tumor immunosuppressive phenotypes, characterized by significantly decreased CD4+ IFNγ+ and CD8+ GZMB+ cytotoxic T cells along with a significantly elevated CD4+ FOXP3+ regulatory T cells. Furthermore, the cytotoxic cytokine IFNγ was significantly reduced in lungs of CCS- (7-fold) and ECV-exposed (2-fold) mice compared to room air-exposed controls. We also found increased levels of the immunosuppressive cytokine IL-10 in lungs of CCS- and ECV-exposed mice. Previous studies have shown IL-10 to play an important role in microbiome-associated immune modulation, hence we performed a preliminary gut and lung microbiome study to assess microbiome dissimilarity in these cohorts. Taxonomic profiling via 16S rRNA gene sequencing of matched stool and lung samples showed differences in the relative abundance of several lung Proteobacteria spp. while gut Firmicutes, particularly Turicibacter and Ileibacterium, were increased by CCS and ECV. In conclusion, while both CCS and ECV increased immune suppression, ECV did not significantly promote tumorigenesis during this timeframe of intervention. Future studies probing differences in microbiome-modulated CCS and ECV immune dysfunction can help pave way for identification of new targets that foster new interception and early treatment strategies for K-ras mutant lung cancer. Citation Format: Walter V. Velasco Torrez, Maria T. Grimaldo, Michael J. Clowers, Bo Yuan, Segundo del Aguila Soto, Iman Bouchelkia, Javier Eduardo Moreno Barragan, Umesh C. Karandikar, Joseph F. Petrosino, Florencia McAllister, Humam Kadara, Kristi Louise Hoffman, Seyed Javad Moghaddam. Comparative effects of combustible cigarette versus electronic cigarette exposures on K-ras mutant lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 649.