title: Human Pancreatic Cancer Cells Induce a MyD88-Dependent Stromal Response to Promote a Tumor-Tolerant Immune Microenvironment.
abstract: Cancer cells exert mastery over the local tumor-associated stroma (TAS) to configure protective immunity within the tumor microenvironment. The immunomodulatory character of pancreatic lysates of patients with cancer differs from those with pancreatitis. In this study, we evaluated the cross-talk between pancreatic cancer and its TAS in primary human cell culture models. Upon exposure of TAS to pancreatic cancer cell-conditioned media, we documented robust secretion of IL6 and IL8. This TAS response was MyD88-dependent and sufficient to directly suppress both CD4+and CD8+T-cell proliferation, inducing Th17 polarization at the expense of Th1. We found that patients possessed a similar shift in circulating effector memory Th17:Th1 ratios compared with healthy controls. The TAS response also directly suppressed CD8+T-cell-mediated cytotoxicity. Overall, our results demonstrate how TAS contributes to the production of an immunosuppressive tumor microenvironment in pancreatic cancer. Cancer Res; 77(3); 672-83. ©2016 AACR.
authors.affiliation: Department of Surgery, University of Florida, Gainesville, Florida.
authors.forename: Daniel
authors.initials: D
authors.lastname: Delitto
authors.affiliation: Department of Oral Biology, University of Florida, Gainesville, Florida.
authors.forename: Andrea E
authors.initials: AE
authors.lastname: Delitto
authors.affiliation: Department of Oral Biology, University of Florida, Gainesville, Florida.
authors.forename: Bayli B
authors.initials: BB
authors.lastname: DiVita
authors.affiliation: Department of Pathology, Immunology, Laboratory Medicine, University of Florida, Gainesville, Florida.|Department of Pathology and Laboratory Medicine, Rutgers New Jersey Medical School and Rutgers Robert Wood Johnson Medical School, Newark, New Jersey.
authors.forename: Kien
authors.initials: K
authors.lastname: Pham
authors.affiliation: Department of Surgery, University of Florida, Gainesville, Florida.
authors.forename: Song
authors.initials: S
authors.lastname: Han
authors.affiliation: Department of Oral Biology, University of Florida, Gainesville, Florida.
authors.forename: Emily R
authors.initials: ER
authors.lastname: Hartlage
authors.affiliation: Department of Pathology, Immunology, Laboratory Medicine, University of Florida, Gainesville, Florida.
authors.forename: Brittney N
authors.initials: BN
authors.lastname: Newby
authors.affiliation: Department of Surgery, University of Florida, Gainesville, Florida.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Gerber
authors.affiliation: Department of Surgery, University of Florida, Gainesville, Florida.
authors.forename: Kevin E
authors.initials: KE
authors.lastname: Behrns
authors.affiliation: Department of Surgery, University of Florida, Gainesville, Florida.
authors.forename: Lyle L
authors.initials: LL
authors.lastname: Moldawer
authors.affiliation: Department of Surgery, University of Florida, Gainesville, Florida.
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Thomas
authors.affiliation: Department of Medicine, University of Florida, Gainesville, Florida.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: George
authors.affiliation: Department of Pathology, Immunology, Laboratory Medicine, University of Florida, Gainesville, Florida.
authors.forename: Todd M
authors.initials: TM
authors.lastname: Brusko
authors.affiliation: Department of Pathology, Immunology, Laboratory Medicine, University of Florida, Gainesville, Florida.
authors.forename: Clayton E
authors.initials: CE
authors.lastname: Mathews
authors.affiliation: Department of Pathology, Immunology, Laboratory Medicine, University of Florida, Gainesville, Florida.|Department of Pathology and Laboratory Medicine, Rutgers New Jersey Medical School and Rutgers Robert Wood Johnson Medical School, Newark, New Jersey.
authors.forename: Chen
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Surgery, University of Florida, Gainesville, Florida.
authors.forename: Jose G
authors.initials: JG
authors.lastname: Trevino
authors.affiliation: Department of Surgery, University of Florida, Gainesville, Florida. swallet@dental.ufl.edu steven.hughes@surgery.ufl.edu.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Hughes
authors.affiliation: Department of Oral Biology, University of Florida, Gainesville, Florida. swallet@dental.ufl.edu steven.hughes@surgery.ufl.edu.
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Wallet
mesh_terms: D002469:Cell Separation; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000276:immunology* / Q000473:pathology*; D060888:Real-Time Polymerase Chain Reaction; D020239:Receptor Cross-Talk / Q000502:physiology; D014407:Tumor Cells, Cultured; D019139:Tumor Escape / Q000276:immunology*; D059016:Tumor Microenvironment / Q000276:immunology*
chemical_list: C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88