title: Expression of the homeobox gene HOXA9 in ovarian cancer induces peritoneal macrophages to acquire an M2 tumor-promoting phenotype.
abstract: Tumor-associated macrophages (TAMs) exhibit an M2 macrophage phenotype that suppresses anti-tumor immune responses and often correlates with poor outcomes in patients with cancer. Patients with ovarian cancer frequently present with peritoneal carcinomatosis, but the mechanisms that induce naïve peritoneal macrophages into TAMs are poorly understood. In this study, we found an increased abundance of TAMs in mouse i.p. xenograft models of ovarian cancer that expressed HOXA9, a homeobox gene that is associated with poor prognosis in patients with ovarian cancer. HOXA9 expression in ovarian cancer cells stimulated chemotaxis of peritoneal macrophages and induced macrophages to acquire TAM-like features. These features included induction of the M2 markers, CD163 and CD206, and the immunosuppressive cytokines, IL-10 and chemokine ligand 17, and down-regulation of the immunostimulatory cytokine, IL-12. HOXA9-mediated induction of TAMs was primarily due to the combinatorial effects of HOXA9-induced, tumor-derived transforming growth factor-β2 and chemokine ligand 2 levels. High HOXA9 expression in clinical specimens of ovarian cancer was strongly associated with increased abundance of TAMs and intratumoral T-regulatory cells and decreased abundance of CD8(+) tumor-infiltrating lymphocytes. Levels of immunosuppressive cytokines were also elevated in ascites fluid of patients with tumors that highly expressed HOXA9. HOXA9 may, therefore, stimulate ovarian cancer progression by promoting an immunosuppressive microenvironment via paracrine effects on peritoneal macrophages.
authors: Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Song Yi
authors: SY
authors: Ko
authors: Section of Gynecologic Oncology, the Department of Obstetrics and Gynecology, University of Chicago, Chicago, Illinois.
authors: Andras
authors: A
authors: Ladanyi
authors: Section of Gynecologic Oncology, the Department of Obstetrics and Gynecology, University of Chicago, Chicago, Illinois.
authors: Ernst
authors: E
authors: Lengyel
authors: Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address: hnaora@mdanderson.org.
authors: Honami
authors: H
authors: Naora
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D064593:Heterografts; D018398:Homeodomain Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology*; D010641:Phenotype; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D018398:Homeodomain Proteins; C097899:homeobox protein HOXA9