TY - JOUR
T1 - Immune Profile of Exosomes in African American Breast Cancer Patients Is Mediated by Kaiso/THBS1/CD47 Signaling
AU - Ahmed, Md Shakir Uddin
AU - Lord, Brittany D.
AU - Adu Addai, Benjamin
AU - Singhal, Sandeep K.
AU - Gardner, Kevin
AU - Salam, Ahmad Bin
AU - Ghebremedhin, Anghesom
AU - White, Jason
AU - Mahmud, Iqbal
AU - Martini, Rachel
AU - Bedi, Deepa
AU - Lin, Huixian
AU - Jones, Jacqueline D.
AU - Karanam, Balasubramanyanam
AU - Dean-Colomb, Windy
AU - Grizzle, William
AU - Wang, Honghe
AU - Davis, Melissa
AU - Yates, Clayton C.
N1 - Publisher Copyright:
© 2023 by the authors.
PY - 2023/4
Y1 - 2023/4
N2 - African American (AA) women with breast cancer are more likely to have higher inflammation and a stronger overall immune response, which correlate with poorer outcomes. In this report, we applied the nanostring immune panel to identify differences in inflammatory and immune gene expression by race. We observed a higher expression of multiple cytokines in AA patients compared to EA patients, with high expression of CD47, TGFB1, and NFKB1 associated with the transcriptional repressor Kaiso. To investigate the mechanism associated with this expression pattern, we observed that Kaiso depletion results in decreased expression of CD47, and its ligand SIRPA. Furthermore, Kaiso appears to directly bind to the methylated sequences of the THBS1 promotor and repress gene expression. Similarly, Kaiso depletion attenuated tumor formation in athymic nude mice, and these Kaiso-depleted xenograft tissues showed significantly higher phagocytosis and increased infiltration of M1 macrophages. In vitro validation using MCF7 and THP1 macrophages treated with Kaiso-depleted exosomes showed a reduced expression of immune-related markers (CD47 and SIRPA) and macrophage polarization towards the M1 phenotype compared to MCF7 cells treated with exosomes isolated from high-Kaiso cells. Lastly, analysis of TCGA breast cancer patient data demonstrates that this gene signature is most prominent in the basal-like subtype, which is more frequently observed in AA breast cancer patients.
AB - African American (AA) women with breast cancer are more likely to have higher inflammation and a stronger overall immune response, which correlate with poorer outcomes. In this report, we applied the nanostring immune panel to identify differences in inflammatory and immune gene expression by race. We observed a higher expression of multiple cytokines in AA patients compared to EA patients, with high expression of CD47, TGFB1, and NFKB1 associated with the transcriptional repressor Kaiso. To investigate the mechanism associated with this expression pattern, we observed that Kaiso depletion results in decreased expression of CD47, and its ligand SIRPA. Furthermore, Kaiso appears to directly bind to the methylated sequences of the THBS1 promotor and repress gene expression. Similarly, Kaiso depletion attenuated tumor formation in athymic nude mice, and these Kaiso-depleted xenograft tissues showed significantly higher phagocytosis and increased infiltration of M1 macrophages. In vitro validation using MCF7 and THP1 macrophages treated with Kaiso-depleted exosomes showed a reduced expression of immune-related markers (CD47 and SIRPA) and macrophage polarization towards the M1 phenotype compared to MCF7 cells treated with exosomes isolated from high-Kaiso cells. Lastly, analysis of TCGA breast cancer patient data demonstrates that this gene signature is most prominent in the basal-like subtype, which is more frequently observed in AA breast cancer patients.
KW - African Americans
KW - breast cancer
KW - cancer health disparity
KW - CD47
KW - exosomes
KW - immune signaling
KW - inflammation
KW - Kaiso
KW - SIRPA
KW - THBS1
KW - tumor microenvironment
UR - http://www.scopus.com/inward/record.url?scp=85153956601&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85153956601&partnerID=8YFLogxK
U2 - 10.3390/cancers15082282
DO - 10.3390/cancers15082282
M3 - Article
C2 - 37190208
AN - SCOPUS:85153956601
SN - 2072-6694
VL - 15
JO - Cancers
JF - Cancers
IS - 8
M1 - 2282
ER -