Abstract PO-234: Relationship between increased concentrations of circulating chemokines and population differences in tumor biology

Abstract

Abstract Genetic ancestry is a significant determinant of multiple aspects of tumor biology, immunity, and inflammatory responses. In lung cancer, in addition to increased incidence in African American (AA) men compared with other racial and ethnic groups in the US, differences in tumor biology between AAs and European Americans (EAs) have been identified. Natural selection is a strong driver of gene selection leading to population differences that can be linked to geographic and genetic ancestry. A classic example involves the Duffy antigen receptor for chemokines, also known as DARC. Individuals with African ancestry are more likely to lack DARC expression on their red blood cells (also known as Duffy null), as this confers resistance to malaria. Loss of erythrocyte expression of DARC is associated with increased circulating chemokine levels in the CXCR and CCR families as DARC serves as a dummy chemokine reservoir. Additionally, Duffy null individuals have lower circulating neutrophils, known as benign ethnic neutropenia. However, loss of DARC expression is exclusive to erythrocytes in Duffy null individuals. As venous endothelial cells and tumor cells also express DARC, we questioned whether the increased circulating bioavailability of DARC ligands in AAs led to increased DARC- dependent signaling in the tumor microenvironment (TME) of AA lung cancer patients. DARC expression on tumor cells is associated with increased aggressiveness and invasion, and endothelial cells have been shown to transcytose DARC ligands into the luminal space. As DARC ligands are associated with angiogenesis and granulocyte recruitment, we hypothesized that tumors of AAs would present with increased blood vessel invasion and granulocyte recruitment to the TME. Using the Somalogic multiplex proteomic assay, we observed significantly elevated levels of the ELR+ CXCR chemokines, with the exception of IL-8 (CXCL8), in serum samples from AA healthy control and stage 1 lung adenocarcinoma patients compared with EAs (samples from the NCI-UMD Case-Control Study), We did not find any evidence of increased angiogenesis as measured by CD31 immunohistochemical staining in AA patients (n= 39) compared with EA patients (n= 107). Immune cell composition did not differ between AAs and EAs as measured by CIBERSORT analysis in both healthy controls and patients between AAs and EAs. Therefore, while AAs have significantly higher levels of circulating DARC ligands compared with EAs, they do not appear to contribute to increased DARC-dependent signaling in normal and tumor lung tissue microenvironment in AAs. Citation Format: Sheryse Taylor, Julian Candia, Adriana Zingone, John Tsang, Brid Ryan. Relationship between increased concentrations of circulating chemokines and population differences in tumor biology [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-234.