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 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 6

Blockade of MDSC recruitment inhibits metastasis.

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Blockade of MDSC recruitment inhibits metastasis. (A, left) Representati...
(A, left) Representative lung images of tumor-bearing mice show RFP+ nodules (red arrows) upon indicated treatments. HCC1806 tumor cells (2 × 105) were injected into mice. Treatment of mice was started 2 days before injection of tumor cells. (A, right) Flow analysis shows the quantification of metastasized RFP+ tumor cells to the lung. (B) Representative IHC images of primary tumor show CD31+ blood vessels in treated and untreated HCC1806 tumors; quantification is shown at right. (C) HCC1806 tumor cells (2 × 105) were injected into the tail vein of NSG mice. RFP+ metastatic lung nodules upon indicated treatments are shown (red arrows). Quantification of RFP+ metastatic lung nodules is shown at right. (D) Representative IF images show the recruitment of S100A8+ cells in the lung upon tail vein injection of HCC1806 cells with indicated treatment (left) and quantification of S100A8+ cells (right). Tumor cells are stained with K14 (green). n is indicated in scatter plots. Scale bars: 500 μm (A and C) and 80 μm (B and D). *P < 0.05, **P < 0.01, ***P < 0.001. (A–D) P values were calculated using 1-way ANOVA with Tukey’s multiple-comparisons post hoc test. Data are presented as the mean ± SEM. (B) n = 3 samples were used, and several random fields per sample were evaluated for quantification from 3 independent experiments.