Abstract Background: Non-small cell lung cancer (NSCLC) exhibits notable disparities between African American (AA) and European American (EA) populations, both in incidence and clinical outcomes. Among the molecular regulators of NSCLC, the CCL20–CCR6 chemokine axis is known to promote tumor progression, metastasis, and immune evasion. CCL20, the natural ligand for CCR6, binds to its receptor CCR6 to recruit immune cells, including regulatory T cells and myeloid suppressor cells. Smoking alters chemokine expression and mutation patterns, but the race-specific impact of CCL20 mutations on receptor engagement and immune signaling remains poorly understood. Methods: Genomic variants of CCL20 were retrieved from the AllofUs and ClinVar databases, categorized by smoking status and race, and modeled using the 6WWZ PDB structure. A split MD strategy in Desmond was implemented to simulate longer-timescale interactions and potential ligand dissociation events, running multiple consecutive trajectories for 1 microsecond (1000ns) per variant. This enabled measurement of residence time through contact duration and structural stability. Key structural metrics were used to compare AA- and EA-derived mutations, including RMSF, average contacts per frame, binding cavity retention (Å3), and SASA. Kinetic metrics such as radius of gyration and ligand-receptor center-of-mass distance were analyzed to quantify the dynamic stability. CCR6 membrane topology was annotated using TMHMM to contextualize variant positions and their functional implications. Results: Our data show a positive correlation between smoking status and mutation frequency in CCL20, which is a natural ligand of CCR6. Mutations in CCL20 (TYR36HIS and GLN26ARG) are significantly more frequent in AA smokers compared to European Americans (EA). AA smoking induced variants showed increased binding cavity volume (412.3 ± 18.6 Å3 vs. 364.7 ± 16.1 Å3 in EA), reduced RMSF at the binding interface (1.12 Å vs. 1.57 Å), and a higher average of hydrogen bonds (4 persistent contacts per frame) with CCR6 across 1-microsecond cumulative simulation window. CCR6-CCL20 contact duration was higher in AA (750 ms) compared to EA (420 ms). Binding interface area retention was higher in AA profiles (3125.9 Å2) than in EA (2758.4 Å2). Conclusion: Our study reveals that smoking-associated CCL20 mutations contribute to higher ligand diversity in AA compared to EA; hence, observed disparities in NSCLC may be due to differential activation of CCR6. Citation Format: Murugesh Eswaran, Briana A. Brock, Hina Mir, Sejong Bae, Gabriela Oprea-Ilies, Eric L. Flenaugh, Sanjai Jain, Brian M. Rivers, Rick Kittles, James W. Lillard Jr, Rajesh Singh, Shailesh Singh. Differential binding affinity of CCL20 with CCR6 due to smoking-induced mutation contributes to disparity in non-small cell lung cancer abstract. In: Proceedings of the 18th AACR Conference on the Science of Cancer Health Disparities; 2025 Sep 18-21; Baltimore, MD. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2025;34(9 Suppl):Abstract nr C011.
Eswaran et al. (Thu,) studied this question.