TY - JOUR
T1 - Δnp63-driven recruitment of myeloid-derived suppressor cells promotes metastasis in triple-negative breast cancer
AU - Kumar, Sushil
AU - Wilkes, David W.
AU - Samuel, Nina
AU - Blanco, Mario Andres
AU - Nayak, Anupma
AU - Alicea-Torres, Kevin
AU - Gluck, Christian
AU - Sinha, Satrajit
AU - Gabrilovich, Dmitry
AU - Chakrabarti, Rumela
N1 - Publisher Copyright:
© 2018 American Society for Clinical Investigation. All rights reserved.
PY - 2018/11/1
Y1 - 2018/11/1
N2 - Triple-negative breast cancer (TNBC) is particularly aggressive, with enhanced incidence of tumor relapse, resistance to chemotherapy, and metastases. As the mechanistic basis for this aggressive phenotype is unclear, treatment options are limited. Here, we showed an increased population of myeloid-derived immunosuppressor cells (MDSCs) in TNBC patients compared with non-TNBC patients. We found that high levels of the transcription factor ΔNp63 correlate with an increased number of MDSCs in basal TNBC patients, and that ΔNp63 promotes tumor growth, progression, and metastasis in human and mouse TNBC cells. Furthermore, we showed that MDSC recruitment to the primary tumor and metastatic sites occurs via direct ΔNp63-dependent activation of the chemokines CXCL2 and CCL22. CXCR2/CCR4 inhibitors reduced MDSC recruitment, angiogenesis, and metastasis, highlighting a novel treatment option for this subset of TNBC patients. Finally, we found that MDSCs secrete prometastatic factors such as MMP9 and chitinase 3-like 1 to promote TNBC cancer stem cell function, thereby identifying a nonimmunologic role for MDSCs in promoting TNBC progression. These findings identify a unique crosstalk between ΔNp63+ TNBC cells and MDSCs that promotes tumor progression and metastasis, which could be exploited in future combined immunotherapy/chemotherapy strategies for TNBC patients.
AB - Triple-negative breast cancer (TNBC) is particularly aggressive, with enhanced incidence of tumor relapse, resistance to chemotherapy, and metastases. As the mechanistic basis for this aggressive phenotype is unclear, treatment options are limited. Here, we showed an increased population of myeloid-derived immunosuppressor cells (MDSCs) in TNBC patients compared with non-TNBC patients. We found that high levels of the transcription factor ΔNp63 correlate with an increased number of MDSCs in basal TNBC patients, and that ΔNp63 promotes tumor growth, progression, and metastasis in human and mouse TNBC cells. Furthermore, we showed that MDSC recruitment to the primary tumor and metastatic sites occurs via direct ΔNp63-dependent activation of the chemokines CXCL2 and CCL22. CXCR2/CCR4 inhibitors reduced MDSC recruitment, angiogenesis, and metastasis, highlighting a novel treatment option for this subset of TNBC patients. Finally, we found that MDSCs secrete prometastatic factors such as MMP9 and chitinase 3-like 1 to promote TNBC cancer stem cell function, thereby identifying a nonimmunologic role for MDSCs in promoting TNBC progression. These findings identify a unique crosstalk between ΔNp63+ TNBC cells and MDSCs that promotes tumor progression and metastasis, which could be exploited in future combined immunotherapy/chemotherapy strategies for TNBC patients.
UR - http://www.scopus.com/inward/record.url?scp=85055841541&partnerID=8YFLogxK
U2 - 10.1172/JCI99673
DO - 10.1172/JCI99673
M3 - Article
C2 - 30295647
AN - SCOPUS:85055841541
SN - 0021-9738
VL - 128
SP - 5095
EP - 5109
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 11
ER -