Abstract 5259: Unraveling the impact of smoking behavior on the immune landscape of prostate cancer

Abstract Smoking is a significant modifiable risk factor for prostate cancer (PCa) diagnosis, recurrence, and mortality. Immune cells play crucial role in cancer-associated inflammation, having a significant impact on tumor fate from early neoplastic transformation to metastatic spread and influencing treatment outcomes. We hypothesize that, in addition to causing carcinogenic mutations, tobacco smoke alters the tumor microenvironment to promote tumor progression. In this study, we examined the effect of smoking behavior on the immune landscape of prostate tumors by performing multiplex gene expression analysis of various immune cell types using the nanoString nCounter® PanCancer immune profiling panel. A total of 24 prostate tumor tissues (Gleason’s score: 7-8) were analyzed, including 12 from never smokers, 7 from current smokers, and 5 former smokers. Unsupervised hierarchical clustering based on the immune scores from different immune cell types grouped PCa samples into two major clusters, representing low and high immune cell infiltration. A higher proportion of current smokers were grouped in the high immune infiltration cluster, whereas never smokers and former smokers predominantly fell into low immune infiltration cluster. In direct comparisons, significantly higher infiltration of tumor-associated macrophages (TAM) (p=0.037) and regulatory T cells (Tregs) (p=0.046) was observed in current smokers compared to never smokers, with a trend for lower mast cell infiltration (p=0.055). Additionally, a significant positive correlation (r=0.42; p=0.036) was observed between TAM with Tregs infiltration in all samples, with a stronger correlation (r=0.88; p=0.008) in current smokers. A total of 89 differentially expressed genes (DEGs) at a 1.5-fold change cutoff were identified between current and never smokers, with 77 genes being upregulated and 12 downregulated in current smokers. Interestingly, only 17 DEGs were identified between never smokers and former smokers. Pathway analysis of the DEGs in current smokers revealed activation of ‘primary immunodeficiency’ and ‘PD-L1 expression and PD-1 checkpoint’ pathways, while the ‘antigen processing and presentation’ and ‘NF-kappa B signaling’ pathways were repressed. Collectively, these findings suggest that current smokers have a relatively compromised tumor immune microenvironment compared to never and former smokers with PCa, potentially facilitating rapid tumor growth and aggressive progression. These findings also have implications for developing novel immune-based therapeutic interventions for PCa patients based on their smoking behavior. Citation Format: Amod Sharma, Mohammad Aslam Khan, Muhammad Tahir, Ajay P. Singh, Seema Singh. Unraveling the impact of smoking behavior on the immune landscape of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5259.