Abstract B046: Racial differences in CCR9 signaling and its association with disparity in chemotherapeutic response in triple negative breast cancer

Abstract

Abstract African American (AA) women are more frequently diagnosed with Triple Negative Breast Cancer (TNBC) and have a poorer prognosis as compared to European American (EA) women. The standard treatment choice fails to achieve a similar response in AA compared to EA. We hypothesize that CCR9 signaling dictates response to therapeutics, and race-specific differences in CCR9 expression and G protein coupling may be contributing to the disparity in clinical and therapeutic outcomes among the two races. Hence, the focus of this study was to determine the race-specific biological differences in CCR9-CCL25 signaling and its association with the observed disparity in chemotherapeutic response. Our data show differences in G-protein decoupling from CCR9 after activation with its natural ligand, CCL25, in cell lines derived from AA lines (MDA-MB-468 and HCC 1806) compared to EA (HCC 1143 and BT 549). Race-specific differences in G-protein decoupling activate the signaling in promoting stemness; overcoming chemotherapy-induced cell death and high cell, survival collectively plays a crucial role in the chemotherapeutic response. Based on our in vitro results, we tested if blocking CCR9-CCL25 addresses the observed racial difference in chemotherapeutic response. To address this, we developed a xenograft model using TNBC cell lines derived from AA (HCC1806) and EA (MDA-MB-231). Tumor-bearing mice were treated with Carboplatin with or without the CCL25 neutralization antibody. CCL25 neutralization showed a reduction in tumor size in both AA and EA xenografts. This reduction in tumor size was more prominent and statistically significant in EA xenografts (p= 0.01), while the reduction wasn’t significant in AA xenografts (p=0.09). Carboplatin as a single agent effectively reduced tumor size in both AA and EA xenografts, but the response was better in EA (p=0.07) compared to AA. The therapeutic response of Carboplatin was significantly higher when given with an anti-CCL25 neutralization antibody (p=0.001) compared to controls. Carboplatin response was better in AA xenograft after CCL25 neutralization compared to vehicle control, CCL25 neutralization, or Carboplatin alone. In conclusion, our results show that in addition to higher expression, signaling downstream to CCR9 in AA differed from EA primarily due to differential G-protein decoupling. Thus, the difference in CCR9-mediated molecular signaling between AA and EA contributes to the observed racial gap in chemotherapeutic response. Therefore, blocking the CCR9-CCL25 axis is critical to addressing the disparity in chemotherapeutic response and clinical outcome in TNBC. Citation Format: Hina Mir, Rajeev Samant, Shailesh Singh. Racial differences in CCR9 signaling and its association with disparity in chemotherapeutic response in triple negative breast cancer [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B046.