title: Pten null prostate epithelium promotes localized myeloid-derived suppressor cell expansion and immune suppression during tumor initiation and progression.
abstract: Chronic inflammation is known to be associated with prostate cancer development, but how epithelium-associated cancer-initiating events cross talk to inflammatory cells during prostate cancer initiation and progression is largely unknown. Using the Pten null murine prostate cancer model, we show an expansion of Gr-1(+) CD11b(+) myeloid-derived suppressor cells (MDSCs) occurring intraprostatically immediately following epithelium-specific Pten deletion without expansion in hematopoietic tissues. This MDSC expansion is accompanied by sustained immune suppression. Prostatic Gr-1(+) CD11b(+) cells, but not those isolated from the spleen of the same tumor-bearing mice, suppress T cell proliferation and express high levels of Arginase 1 and iNOS. Mechanistically, the loss of PTEN in the epithelium leads to a significant upregulation of genes within the inflammatory response and cytokine-cytokine receptor interaction pathways, including Csf1 and Il1b, two genes known to induce MDSC expansion and immunosuppressive activities. Treatment of Pten null mice with the selective CSF-1 receptor inhibitor GW2580 decreases MDSC infiltration and relieves the associated immunosuppressive phenotype. Our study indicates that epithelium-associated tumor-initiating events trigger the secretion of inflammatory cytokines and promote localized MDSC expansion and immune suppression, thereby promoting tumor progression.
authors.affiliation: Department of Molecular and Medical Pharmacology, Institute for Molecular Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
authors.forename: Alejandro J
authors.initials: AJ
authors.lastname: Garcia
authors.affiliation: Department of Molecular and Medical Pharmacology, Institute for Molecular Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA. Molecular Biology Institute, University of California, Los Angeles, Los Angeles, California, USA
authors.forename: Marcus
authors.initials: M
authors.lastname: Ruscetti
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
authors.forename: Teresita L
authors.initials: TL
authors.lastname: Arenzana
authors.affiliation: Department of Molecular and Medical Pharmacology, Institute for Molecular Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
authors.forename: Linh M
authors.initials: LM
authors.lastname: Tran
authors.affiliation: Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
authors.forename: Daniella
authors.initials: D
authors.lastname: Bianci-Frias
authors.affiliation: Department of Molecular and Medical Pharmacology, Institute for Molecular Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
authors.forename: Elysia
authors.initials: E
authors.lastname: Sybert
authors.affiliation: Department of Molecular and Medical Pharmacology, Institute for Molecular Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
authors.forename: Saul J
authors.initials: SJ
authors.lastname: Priceman
authors.affiliation: Department of Molecular and Medical Pharmacology, Institute for Molecular Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
authors.forename: Lily
authors.initials: L
authors.lastname: Wu
authors.affiliation: Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
authors.forename: Peter S
authors.initials: PS
authors.lastname: Nelson
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Smale
authors.affiliation: Department of Molecular and Medical Pharmacology, Institute for Molecular Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA. School of Life Sciences, PKU-Tsinghua Center for Life Sciences, Peking University, Beijing, China
authors.forename: Hong
authors.initials: H
authors.lastname: Wu
mesh_terms: D000818:Animals; D000840:Anisoles / Q000494:pharmacology; D001119:Arginase / Q000096:biosynthesis; D039481:CD11b Antigen / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004195:Disease Models, Animal; D004848:Epithelium / Q000276:immunology / Q000473:pathology; D007108:Immune Tolerance; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D053583:Interleukin-1beta / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000276:immunology; D016173:Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000276:immunology / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D011467:Prostate / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000276:immunology*; D011743:Pyrimidines / Q000494:pharmacology; D019707:Receptors, Chemokine / Q000378:metabolism; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D015854:Up-Regulation
chemical_list: C506269:5-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)pyrimidine-2,4-diamine; D000840:Anisoles; D039481:CD11b Antigen; C503133:Gr-1 protein, mouse; C587672:IL1B protein, mouse; D053583:Interleukin-1beta; D011743:Pyrimidines; D019707:Receptors, Chemokine; D016173:Macrophage Colony-Stimulating Factor; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; C544448:Arg1 protein, mouse; D001119:Arginase