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 7

MDSCs secrete prometastatic factors and enhance CSC activities of TNBC.

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MDSCs secrete prometastatic factors and enhance CSC activities of TNBC. ...
(A and B) Number (A) and representative images (B) of tumorspheres from HCC1806 cells cultured for 3 days with or without MDSCs. (C and D) Number (C) and representative images (D) of tumorspheres from SUM159 cells cultured for 3 days with or without MDSCs. (A–D) n = 3 independent experiments performed in technical duplicate. (E) Representative images of cytokine arrays from cell lysates of normal mammary neutrophils (from mammary gland) and MDSCs from primary mammary tumor. (F) Table shows the most differentially expressed proteins. (G) Representative array blots show differential protein expression upon treatment of MDSCs with recombinant CXCL2 and CCL22 for 12 hours. (H) Scatter plot shows number of tumorspheres from HCC1806 cells upon indicated treatments. Scatter plot show data from 3 independent experiments, and data are presented as the mean ± SEM. (I) Model shows the recruitment of PMN-MDSCs at primary tumor and at metastatic organ via ΔNp63+ cancer cells through chemokines. Concomitantly, MDSCs secrete factors such as chitinase 3–like 1 (CHI3L1) and MMP9 to enhance both tumor growth and metastatic potential. Scale bars: 40 μm (B and D). Data are presented as the mean ± SEM. *P < 0.05; **P < 0.01. P value was calculated using 1-way ANOVA with Tukey’s multiple-comparisons post hoc test.