The role of African Duffy-null allele related inflammation on the tumor microenvironment
Recommended Citation
Guerra Y, Martini R, Bensenhaver J, Chen Y, Oppong JK, Kyei I, Aitpillah FS, Adinku MO, Oppong JK, Adjei EK, Jibril A, Awuah B, Bekele M, Abebe E, Ankomah K, Osei-Bonsu EB, Gyan KK, Yates C, Blenman K, Elemento O, Newman L, Davis MB. The role of African Duffy-null allele related inflammation on the tumor microenvironment. Cancer Epidemiol Biomarkers Prev 2022; 31(1 SUPPL).
Document Type
Conference Proceeding
Publication Date
1-1-2022
Publication Title
Cancer Epidemiol Biomarkers Prev
Abstract
DARC/ACKR1 erythrocyte expression, also known as the “Duffy blood group,” is understood to sequester pro-inflammatory chemokines and thereby regulate circulating gradients that direct immune cell infiltration. We hypothesize that this function also determines immune cell landscapes in the tumor microenvironment. Due to evolutionary selection pressures of malaria, individuals with sub-Saharan African ancestry typically carry the Duffy-null allele (rs4849887) and this lack of DARC/ACKR1 expression gives immunity to malaria while also allowing chronically high inflammation levels. Over 68% of African Americans (AA) have been found to have the Duffy-null genotype, compared to a rare 1-3% in European American individuals and we have shown it increases predisposition for Triple-Negative Breast Cancer (TNBC). In addition, we are currently studying if Duffy-null may contribute to higher breast cancer mortality that disproportionately affects AA women. This may be in part due to the role that low-DARC/ACKR1 expression plays in chronic inflammation, altering levels of several chemokines that modulate the migration and differentiation of specific immune cells. This role will impact tumor immune cell infiltration as well as the immune cell population composition overall, depending upon levels of DARC/ACKR1. Using RNA sequencing, our initial results indicated that for breast cancer tumors with high DARC/ACKR1 expression there was a higher estimated presence of CD8+ T cells, CD4+ T cells, regulatory T cells, follicular helper T cells, and memory B cells. Whereas with low DARC/ACKR1 expression, there was markedly less expression of resting dendritic cells and memory B cells. Therefore, in order to ascertain the influence DARC status has on spatial deposition and functional status of immune cell landscapes across the tumor microenvironment, we performed imaging mass cytometry on primary TNBC tumors. The panel contained tumor, structural, and immune markers, and was used to characterize the spatial differences between samples that had been verified to be DARC-high or DARC-low through immunohistochemistry. Our imaging analyses indicated that high DARC/ACKR1 expression correlates with infiltration of monocytes, macrophages, and cytotoxic T cells into the solid tumor microenvironment. Conversely, tumors with low DARC/ACKR1 expression showed monocytes and cytotoxic T cells contained in the tumor stroma. Using single-cell phenotyping, we were also able to identify distinct cell populations between DARC-high and -low. The tSNE analysis and heatmaps performed using Histology Topography Cytometry Analysis Toolbox (histoCAT), allowed us to visualize the spatial distribution of these cell populations, indicating an immune-suppressive tumor microenvironment in DARC-low tumors. These differences may be implicated in the causality of tumor progression as well as how to approach treatment given the cell heterogeneity of TNBC. This work provides greater context on the role that Duffy-null plays in chronic inflammation on the tumor microenvironment.
Medical Subject Headings
Hematology
PubMed ID
Not assigned.
Volume
31
Issue
1 SUPPL
