Abstract B39: Distinct recruitment of tumor-associated immune cells correlates with increased pro-malignant chemokines in tumors expressing epithelial Atypical Chemokine Receptor 1 (ACKR1/DARC)
Authors: Jenkins Brittany D. , Martini Rachel N. , Hire Rupali , Monteil Michele A. , Davis Melissa B. 
Published: March 2017

The tumor microenvironment is a complex heterogeneous mixture of cancer cells, immune cells, and many other cell types contributing to a myriad of clinical outcomes for breast cancer (BrCa) patients. Chemokine receptors play an important role in maintaining the homeostasis of pro-inflammatory chemokines, and, in turn, help direct the migration of tumor-associated immune cells. Atypical chemokine receptors, such as the Atypical Chemokine Receptor 1 (ACKR1/DARC), act to sequester chemokine activity and control leukocyte migration during tumor-associated inflammation. ACKR1 is unique in that its associated gene carries a fixed mutation in African populations, causing the receptor to not be expressed on red blood cells as a response to endemic malaria in Africa. It is well-known that African-Americans in the United States tend to develop more aggressive BrCa subtypes, and as a result, experience more deaths per year from BrCa related causes. The purpose of this study is to characterize this disparity by investigating the distinct migration of tumor-associated immune cells between ACKR1 positive and negative tumors. We also wish to determine any correlations between ACKR1 and pro-inflammatory chemokines in various BrCa cell types. Using immunohistochemistry, relative expression levels were determined for ACKR1, cytotoxic T-cells, B-cells, dendritic cells, and macrophages in primary breast tumor samples. The levels of pro-inflammatory chemokines in circulation were determined using a Luminex immuno-assay on peripheral blood samples. Localization of ACKR1-associated chemokines was also investigated using immunofluorescence. Initial results from our study cohort indicate differential expression of immune cells on tumors expressing ACKR1, leading to a unique tumor microenvironment. We observed that ACKR1 positive tumors recruited B-cells and dendritic cells, whereas, ACKR1 negative tumors did not. Also, we found a positive correlation between ACKR1 expression in tumor tissue, and expression of CCL2 (MCP-1) and CXCL8 (IL-8) in the peripheral blood of our cancer patients. Finally, a strong co-localization of ACKR1 with CCL2 and CXCL8 was observed in cultured mammalian breast cancer cells. Overall, our pilot data suggests that the presence of ACKR1 on tumor cells changes the tumor microenvironment by recruiting a distinct subset of immune cells and pro-inflammatory chemokines to the area of inflammation.

Citation Format: Brittany D. Jenkins, Rachel N. Martini, Rupali Hire, Michele A. Monteil, Melissa B. Davis. Distinct recruitment of tumor-associated immune cells correlates with increased pro-malignant chemokines in tumors expressing epithelial Atypical Chemokine Receptor 1 (ACKR1/DARC). [abstract]. In: Proceedings of the Ninth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2016 Sep 25-28; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(2 Suppl):Abstract nr B39.