ΔNp63-driven recruitment of myeloid-derived suppressor cells promotes metastasis in triple-negative breast cancer
Sushil Kumar, David W. Wilkes, Nina Samuel, Mario Andres Blanco, Anupma Nayak, Kevin Alicea-Torres, Christian Gluck, Satrajit Sinha, Dmitry Gabrilovich, Rumela Chakrabarti
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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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 3

ΔNp63 promotes recruitment of MDSCs at primary tumor and metastatic site.

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ΔNp63 promotes recruitment of MDSCs at primary tumor and metastatic site...
(A) Flow profile of CD45+ population of control and ΔNp63-KD HCC1806 tumor based on the staining of CD11B and Gr1 markers shows MDSC population. Fluorescence Minus One (FMO) negative control is shown in Supplemental Figure 7A. (B–D) Flow cytometric analysis depicts percentage of MDSCs (CD11B+Gr1+F4/80–) (B), macrophages (CD45+F4/80+) (C), and dendritic cells (DCs; CD45+CD11c+) (D) in primary tumors of indicated groups. (E and F) Flow cytometric analysis depicting MDSC subpopulations: PMN-MDSCs (CD45+CD11B+Ly6G+) (E) and M-MDSCs (CD45+CD11B+Ly6C+) (F). n is indicated in scatter plots for different groups in B–F. (G and H) Representative IF images show S100A8+ stained myeloid cells at the primary tumor (G) and metastatic site (H) of control and ΔNp63-KD HCC1806 cells. Scatter plots to the right show quantification of S100A8+ cells per FOV. (I and J) IF images show myeloid cells in primary tumor (I) and at metastatic site (J) of control and ΔNp63-KD SUM159 cells. Scatter plots to the right show quantification of S100A8+ cells. Scale bars: 40 μm (G–J). **P < 0.01, ***P < 0.001, #NS. Data are presented as the mean ± SEM. (B–J) Student’s t test was used to compute P values. (G–J) n = 3 samples were used, and several random fields were evaluated per sample for quantification from 3 independent experiments.