ΔNp63-driven recruitment of myeloid-derived suppressor cells promotes metastasis in triple-negative breast cancer
Sushil Kumar, … , Dmitry Gabrilovich, Rumela Chakrabarti
Sushil Kumar, … , Dmitry Gabrilovich, Rumela Chakrabarti
Published November 1, 2018; First published October 8, 2018
Citation Information: J Clin Invest. 2018;128(11):5095-5109. https://doi.org/10.1172/JCI99673.
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Research Article Oncology

ΔNp63-driven recruitment of myeloid-derived suppressor cells promotes metastasis in triple-negative breast cancer

Abstract

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.

Authors

Sushil Kumar, David W. Wilkes, Nina Samuel, Mario Andres Blanco, Anupma Nayak, Kevin Alicea-Torres, Christian Gluck, Satrajit Sinha, Dmitry Gabrilovich, Rumela Chakrabarti

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Figure 1

TNBC contains higher MDSC infiltration and high expression of ΔNp63, which is associated with reduced distant metastasis–free survival of human patients.

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TNBC contains higher MDSC infiltration and high expression of ΔNp63, whi...
(A and B) Representative immunofluorescence (IF) images (left) and calculated abundance (right) for CD33 and S100A9 (A) and CD15 and Lox-1 (B). Increased costaining of CD33 and S100A9 (yellow) in TNBC patients indicates increased MDSCs in these patients. Increased costaining of Lox-1 and CD15 (yellow cells indicated with white arrowheads) further confirms that MDSCs in TNBC are PMN-MDSCs. (C) Representative IHC images (left) and calculated H-score (right) for ΔNp63 expression in patient tissues. The H-score value is the product of abundance of cells expressing respective protein (scale of 0–100) multiplied by the intensity of expression of that protein (scale of 0–3). (D and E) Box plot shows higher infiltration of MDSC (D) and PMN-MDSC (E) positivity in ΔNp63-high (ΔNhigh) than in ΔNp63-low (ΔNlow) human TNBC tumor samples. ΔNhigh and ΔNlow patients were stratified based on being above or below the median of ΔNp63 H-score in C. (A and B) Non-TNBC, n = 21 patient samples; TNBC, n = 22 patient samples. (D and E) TNBC, n = 22 patient samples. (F–H) High p63 (TP63) expression correlates with reduced distant metastasis–free survival (DMFS) in ER–PR– (F), TNBC (G), but not non-TNBC (H) clinical samples in the KM Plotter breast cancer database (30). Scale bars: 40 μm (A–C). (A–E) Mann-Whitney U test was used for scatter dot plots to quantify the difference between respective protein expressions. (F–H) Log-rank test was used for KM plots to calculate P value.