Myeloid-Derived Suppressor Cells Endow Stem-like Qualities to Breast Cancer Cells through IL6/STAT3 and NO/NOTCH Cross-talk Signaling.

Abstract

Myeloid-derived suppressor cells (MDSC) contribute to immune suppression in cancer, but the mechanisms through which they drive metastatic progression are not fully understood. In this study, we show how MDSC convey stem-like qualities to breast cancer cells that coordinately help enable immune suppression and escape. We found that MDSC promoted tumor formation by enhancing breast cancer cell stem-like properties as well as by suppressing T-cell activation. Mechanistic investigations indicated that these effects relied upon cross-talk between the STAT3 and NOTCH pathways in cancer cells, with MDSC inducing IL6-dependent phosphorylation of STAT3 and activating NOTCH through nitric oxide leading to prolonged STAT3 activation. In clinical specimens of breast cancer, the presence of MDSC correlated with the presence of cancer stem-like cells (CSC) and independently predicted poor survival outcomes. Collectively, our work revealed an immune-associated mechanism that extrinsically confers cancer cell stemness properties and affects patient outcome. We suggest that targeting STAT3-NOTCH cross-talk between MDSC and CSC could offer a unique locus to improve cancer treatment, by coordinately targeting a coupled mechanism that enables cancer stemness and immune escape. Cancer Res; 76(11); 3156-65. ©2016 AACR.

• Authors: Dongjun Peng, Takashi Tanikawa, Wei Li, Lili Zhao, Linda Vatan, Wojciech Szeliga, Shanshan Wan, Shuang Wei, Yin Wang, Yan Liu, Elzbieta Staroslawska, Franciszek Szubstarski, Jacek Rolinski, Ewelina Grywalska, Andrzej Stanisławek, Wojciech Polkowski, Andrzej Kurylcio, Celina Kleer, Alfred E Chang, Max Wicha, Michael Sabel, Weiping Zou, Ilona Kryczek
• Journal: Cancer research (Cancer Res) Vol. 76 Issue 11 Pg. 3156-65 (06 01 2016) ISSN: 1538-7445 [Electronic] United States
• PMID: 27197152 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: ©2016 American Association for Cancer Research.

Chemical References

• Interleukin-6
• RNA, Messenger
• Receptors, Notch
• STAT3 Transcription Factor
• Nitric Oxide

Topics

• Animals
• Apoptosis
• Blotting, Western
• Breast Neoplasms (genetics, metabolism, pathology)
• Cell Proliferation
• Cohort Studies
• Female
• Flow Cytometry
• Follow-Up Studies
• Humans
• Immunoenzyme Techniques
• Interleukin-6 (genetics, metabolism)
• Lymphocyte Activation
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Myeloid-Derived Suppressor Cells (metabolism, pathology)
• Neoplasm Staging
• Neoplastic Stem Cells (metabolism, pathology)
• Nitric Oxide (metabolism)
• Phosphorylation
• Prognosis
• RNA, Messenger (genetics)
• Real-Time Polymerase Chain Reaction
• Receptor Cross-Talk
• Receptors, Notch (genetics, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• STAT3 Transcription Factor (genetics, metabolism)
• Signal Transduction
• Survival Rate
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays