Abstract 2504: Activation of alternative receptor by CCL5 is associated with non-small cell lung cancer disparities

Abstract Background and Significance: Lung cancer remains the leading cause of cancer-related mortality in the United States, with persistently lower survival rates among African Americans (AAs) compared to European Americans (EAs). Emerging evidence suggests that race-associated molecular differences in chemokine receptor-ligand networks may underlie these disparities. Chemokine signaling through CC chemokine receptor 5 (CCR5) and its ligand CCL5 has been implicated in tumor growth and immune modulation; however, chemokine ligands often exhibit receptor promiscuity. Hence, in this study, we have demonstrated the activation of other chemokine receptors when CCL5 is unable to activate CCR5, as well as its association with disparities in NSCLC. Methods: An ELISA assay was used to quantify CCL5, and PCR Immunoprecipitation followed by Western blot was used to evaluate mRNA transcripts and protein expression of CCL5, CCR5, CCR3, and CCR1. An anti-CCR5 antibody and/or a small molecule inhibitor of CCR5 were used during the functional assay, with or without CCL5 stimulation, and blocking other receptors that also share CCL5 as a ligand. Results: Our findings reveal that CCL5-driven signaling in NSCLC is not restricted to CCR5 and that alternative receptor engagement, such as CCR3 activation, may sustain tumor-promoting pathways. The differential expression of chemokine receptors in AA- versus EA-derived lung cancer cells suggests that ligand-receptor selectivity and compensatory signaling could contribute to racial disparities in lung cancer biology and outcomes. Ongoing work targeting CCR3 will determine whether this receptor mediates escape signaling when CCR5 is unavailable, thereby identifying precision-based therapeutic strategies to disrupt redundant chemokine circuits that reinforce tumor progression and inequities in disease burden. Conclusions and Implications: These findings highlight the complexity of chemokine signaling in lung cancer, where ligand promiscuity and receptor redundancy can sustain the proliferation and migration of cancer cells. Differences in CCR3, CCR5, and GPR75 expression, cancer-related gene activity, and migratory behavior in AA and EA-derived cells suggest that differences in chemokine receptor utilization may play a crucial role in shaping the molecular landscape and cellular behaviors that contribute to racial disparities in lung cancer outcomes Citation Format: Briana Alicia Brock, Murugesh Eswaran, Hina Mir, Shailesh Singh. Activation of alternative receptor by CCL5 is associated with non-small cell lung cancer disparities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2504.