title: Dickkopf-related protein 1 (Dkk1) regulates the accumulation and function of myeloid derived suppressor cells in cancer.
abstract: Tumor-stroma interactions contribute to tumorigenesis. Tumor cells can educate the stroma at primary and distant sites to facilitate the recruitment of heterogeneous populations of immature myeloid cells, known as myeloid-derived suppressor cells (MDSCs). MDSCs suppress T cell responses and promote tumor proliferation. One outstanding question is how the local and distant stroma modulate MDSCs during tumor progression. Down-regulation of β-catenin is critical for MDSC accumulation and immune suppressive functions in mice and humans. Here, we demonstrate that stroma-derived Dickkopf-1 (Dkk1) targets β-catenin in MDSCs, thus exerting immune suppressive effects during tumor progression. Mice bearing extraskeletal tumors show significantly elevated levels of Dkk1 in bone microenvironment relative to tumor site. Strikingly, Dkk1 neutralization decreases tumor growth and MDSC numbers by rescuing β-catenin in these cells and restores T cell recruitment at the tumor site. Recombinant Dkk1 suppresses β-catenin target genes in MDSCs from mice and humans and anti-Dkk1 loses its antitumor effects in mice lacking β-catenin in myeloid cells or after depletion of MDSCs, demonstrating that Dkk1 directly targets MDSCs. Furthermore, we find a correlation between CD15(+) myeloid cells and Dkk1 in pancreatic cancer patients. We establish a novel immunomodulatory role for Dkk1 in regulating tumor-induced immune suppression via targeting β-catenin in MDSCs.
authors.affiliation: Department of Orthopedics, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Lucia
authors.initials: L
authors.lastname: D'Amico
authors.affiliation: Department of Orthopedics, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Sahil
authors.initials: S
authors.lastname: Mahajan
authors.affiliation: Department of Orthopedics, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Aude-Hélène
authors.initials: AH
authors.lastname: Capietto
authors.affiliation: Department of Orthopedics, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Zhengfeng
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of Orthopedics, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Ali
authors.initials: A
authors.lastname: Zamani
authors.affiliation: Department of Orthopedics, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Biancamaria
authors.initials: B
authors.lastname: Ricci
authors.affiliation: Department of Orthopedics, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: David B
authors.initials: DB
authors.lastname: Bumpass
authors.affiliation: Department of Medicine Oncology Division, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Melissa
authors.initials: M
authors.lastname: Meyer
authors.affiliation: Department of Medicine Oncology Division, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Xinming
authors.initials: X
authors.lastname: Su
authors.affiliation: Department of Medicine Oncology Division, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Andrea
authors.initials: A
authors.lastname: Wang-Gillam
authors.affiliation: Department of Medicine Oncology Division, Washington University School of Medicine, St. Louis, MO 63110 Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Katherine
authors.initials: K
authors.lastname: Weilbaecher
authors.affiliation: Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110 Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110 ICCE Institute, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Sheila A
authors.initials: SA
authors.lastname: Stewart
authors.affiliation: Department of Medicine Oncology Division, Washington University School of Medicine, St. Louis, MO 63110 Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110 ICCE Institute, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: David G
authors.initials: DG
authors.lastname: DeNardo
authors.affiliation: Department of Orthopedics, Washington University School of Medicine, St. Louis, MO 63110 Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110 faccior@wustl.edu.
authors.forename: Roberta
authors.initials: R
authors.lastname: Faccio
mesh_terms: D000818:Animals; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000276:immunology / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000276:immunology* / Q000473:pathology; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000276:immunology* / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D059016:Tumor Microenvironment / Q000187:drug effects* / Q000276:immunology; D051176:beta Catenin / Q000276:immunology
chemical_list: C501126:DKK1 protein, human; C501127:Dkk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D051176:beta Catenin