title: CD38-Expressing Myeloid-Derived Suppressor Cells Promote Tumor Growth in a Murine Model of Esophageal Cancer.
abstract: Myeloid-derived suppressor cells (MDSC) are an immunosuppressive population of immature myeloid cells found in advanced-stage cancer patients and mouse tumor models. Production of inducible nitric oxide synthase (iNOS) and arginase, as well as other suppressive mechanisms, allows MDSCs to suppress T-cell-mediated tumor clearance and foster tumor progression. Using an unbiased global gene expression approach in conditional p120-catenin knockout mice (L2-cre;p120ctn(f/f)), a model of oral-esophageal cancer, we have identified CD38 as playing a vital role in MDSC biology, previously unknown. CD38 belongs to the ADP-ribosyl cyclase family and possesses both ectoenzyme and receptor functions. It has been described to function in lymphoid and early myeloid cell differentiation, cell activation, and neutrophil chemotaxis. We find that CD38 expression in MDSCs is evident in other mouse tumor models of esophageal carcinogenesis, and CD38(high) MDSCs are more immature than MDSCs lacking CD38 expression, suggesting a potential role for CD38 in the maturation halt found in MDSC populations. CD38(high) MDSCs also possess a greater capacity to suppress activated T cells, and promote tumor growth to a greater degree than CD38(low) MDSCs, likely as a result of increased iNOS production. In addition, we have identified novel tumor-derived factors, specifically IL6, IGFBP3, and CXCL16, which induce CD38 expression by MDSCs ex vivo. Finally, we have detected an expansion of CD38(+) MDSCs in peripheral blood of advanced-stage cancer patients and validated targeting CD38 in vivo as a novel approach to cancer therapy.
authors: Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.
authors: Tatiana A
authors: TA
authors: Karakasheva
authors: Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.
authors: Todd J
authors: TJ
authors: Waldron
authors: Thoracic Surgery Research Laboratory, Department of Surgery, Hospital of the University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.
authors: Evgeniy
authors: E
authors: Eruslanov
authors: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Sang-Bae
authors: SB
authors: Kim
authors: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Ju-Seog
authors: JS
authors: Lee
authors: Thoracic Surgery Research Laboratory, Department of Surgery, Hospital of the University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.
authors: Shaun
authors: S
authors: O'Brien
authors: Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.
authors: Philip D
authors: PD
authors: Hicks
authors: Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania, Philadelphia, Pennsylvania. Surgery Service; Philadelphia Veterans Affairs Medical Center, Philadelphia, Pennsylvania.
authors: Devraj
authors: D
authors: Basu
authors: Thoracic Surgery Research Laboratory, Department of Surgery, Hospital of the University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania. Surgery Service; Philadelphia Veterans Affairs Medical Center, Philadelphia, Pennsylvania.
authors: Sunil
authors: S
authors: Singhal
authors: Lab of Immunogenetics, Department of Medical Sciences, University of Torino Medical School, Torino, Italy.
authors: Fabio
authors: F
authors: Malavasi
authors: Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania. Department of Genetics, University of Pennsylvania, Philadelphia, Pennsylvania. anil2@mail.med.upenn.edu.
authors: Anil K
authors: AK
authors: Rustgi
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000096:biosynthesis / Q000097:blood / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001119:Arginase / Q000502:physiology; D002294:Carcinoma, Squamous Cell / Q000276:immunology* / Q000473:pathology; D045744:Cell Line, Tumor; D016207:Cytokines / Q000502:physiology; D004195:Disease Models, Animal; D004938:Esophageal Neoplasms / Q000276:immunology* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance / Q000502:physiology; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000097:blood / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000737:chemistry / Q000276:immunology*; D038042:Myelopoiesis / Q000502:physiology; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology; D019139:Tumor Escape / Q000276:immunology*; D014410:Tumor Stem Cell Assay
chemical_list: D016207:Cytokines; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C498154:CD38 protein, human; C498155:Cd38 protein, mouse; D051997:ADP-ribosyl Cyclase 1; D001119:Arginase