title: 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.affiliation: Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan.
authors.forename: Dongjun
authors.initials: D
authors.lastname: Peng
authors.affiliation: Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Tanikawa
authors.affiliation: Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Biostatistics, University of Michigan School of Medicine, Ann Arbor, Michigan.
authors.forename: Lili
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan.
authors.forename: Linda
authors.initials: L
authors.lastname: Vatan
authors.affiliation: Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Szeliga
authors.affiliation: Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Wan
authors.affiliation: Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan.
authors.forename: Shuang
authors.initials: S
authors.lastname: Wei
authors.affiliation: Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan.
authors.forename: Yin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: St. John's Cancer Center, Lublin, Poland.
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Staroslawska
authors.affiliation: St. John's Cancer Center, Lublin, Poland.
authors.forename: Franciszek
authors.initials: F
authors.lastname: Szubstarski
authors.affiliation: Department of Clinical Immunology, Medical University of Lublin, Lublin, Poland.
authors.forename: Jacek
authors.initials: J
authors.lastname: Rolinski
authors.affiliation: Department of Clinical Immunology, Medical University of Lublin, Lublin, Poland.
authors.forename: Ewelina
authors.initials: E
authors.lastname: Grywalska
authors.affiliation: Department of Oncology, Medical University of Lublin, Lublin, Poland.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Stanisławek
authors.affiliation: Department of Surgical Oncology, Medical University of Lublin, Lublin, Poland.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Polkowski
authors.affiliation: Department of Surgical Oncology, Medical University of Lublin, Lublin, Poland.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Kurylcio
authors.affiliation: Department of Pathology, University of Michigan School of Medicine, Ann Arbor, Michigan. University of Michigan Comprehensive Cancer Center, University of Michigan School of Medicine, Ann Arbor, Michigan.
authors.forename: Celina
authors.initials: C
authors.lastname: Kleer
authors.affiliation: Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan. University of Michigan Comprehensive Cancer Center, University of Michigan School of Medicine, Ann Arbor, Michigan.
authors.forename: Alfred E
authors.initials: AE
authors.lastname: Chang
authors.affiliation: University of Michigan Comprehensive Cancer Center, University of Michigan School of Medicine, Ann Arbor, Michigan. Department of Medicine, University of Michigan School of Medicine, Ann Arbor, Michigan.
authors.forename: Max
authors.initials: M
authors.lastname: Wicha
authors.affiliation: Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan. University of Michigan Comprehensive Cancer Center, University of Michigan School of Medicine, Ann Arbor, Michigan.
authors.forename: Michael
authors.initials: M
authors.lastname: Sabel
authors.affiliation: Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan. University of Michigan Comprehensive Cancer Center, University of Michigan School of Medicine, Ann Arbor, Michigan. Graduate Programs in Immunology and Tumor Biology, University of Michigan School of Medicine, Ann Arbor, Michigan. wzou@umich.edu ilonak@umich.edu.
authors.forename: Weiping
authors.initials: W
authors.lastname: Zou
authors.affiliation: Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan. wzou@umich.edu ilonak@umich.edu.
authors.forename: Ilona
authors.initials: I
authors.lastname: Kryczek
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D015331:Cohort Studies; D005260:Female; D005434:Flow Cytometry; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D008213:Lymphocyte Activation; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D000072737:Myeloid-Derived Suppressor Cells / Q000378:metabolism / Q000473:pathology*; D009367:Neoplasm Staging; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D009569:Nitric Oxide / Q000378:metabolism*; D010766:Phosphorylation; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020239:Receptor Cross-Talk; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D015850:Interleukin-6; D012333:RNA, Messenger; D051880:Receptors, Notch; D050796:STAT3 Transcription Factor; D009569:Nitric Oxide