title: Downstream mediators of the intratumoral interferon response suppress antitumor immunity, induce gemcitabine resistance and associate with poor survival in human pancreatic cancer.
abstract: The cancer microenvironment allows tumor cells to evade immune surveillance through a variety of mechanisms. While interferon-γ (IFNγ) is central to effective antitumor immunity, its effects on the microenvironment are not as clear and have in some cancers been shown to induce immune checkpoint ligands. The heterogeneity of these responses to IFNγ remains poorly characterized in desmoplastic malignancies with minimal inflammatory cell infiltration, such as pancreatic cancer (PC). Thus, the IFNγ response within and on key cells of the PC microenvironment was evaluated. IFNγ induced expression of human leukocyte antigen (HLA) class I and II on PC cell lines, primary pancreatic cancer epithelial cells (PPCE) and patient-derived tumor-associated stroma, concomitant with an upregulation of PDL1 in the absence of CD80 and CD86 expression. As expected, IFNγ also induced high levels of CXCL10 from all cell types. In addition, significantly higher levels of CXCL10 were observed in PC specimens compared to those from chronic pancreatitis, whereby intratumoral CXCL10 concentration was an independent predictor of poor survival. Immunohistochemical analysis revealed a subset of CXCR3-positive cancer cells in over 90 % of PC specimens, as well as on a subset of cultured PC cell lines and PPCE, whereby exposure to CXCL10 induced resistance to the chemotherapeutic gemcitabine. These findings suggest that IFNγ has multiple effects on many cell types within the PC microenvironment that may lead to immune evasion, chemoresistance and shortened survival.
authors.affiliation: Department of Surgery, College of Medicine, University of Florida, PO BOX 100109, Gainesville, FL, 32610, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Delitto
authors.affiliation: Department of Surgery, College of Medicine, University of Florida, PO BOX 100109, Gainesville, FL, 32610, USA.
authors.forename: Chelsey
authors.initials: C
authors.lastname: Perez
authors.affiliation: Department of Surgery, College of Medicine, University of Florida, PO BOX 100109, Gainesville, FL, 32610, USA.
authors.forename: Song
authors.initials: S
authors.lastname: Han
authors.affiliation: Department of Pathology, Immunology, Laboratory Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: David H
authors.initials: DH
authors.lastname: Gonzalo
authors.affiliation: Department of Pathology, Immunology, Laboratory Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: Kien
authors.initials: K
authors.lastname: Pham
authors.affiliation: Department of Oral Biology, College of Dentistry, University of Florida, PO BOX 100434, Gainesville, FL, 32610, USA.
authors.forename: Andrea E
authors.initials: AE
authors.lastname: Knowlton
authors.affiliation: Department of Oral Biology, College of Dentistry, University of Florida, PO BOX 100434, Gainesville, FL, 32610, USA.
authors.forename: Christina L
authors.initials: CL
authors.lastname: Graves
authors.affiliation: Department of Surgery, College of Medicine, University of Florida, PO BOX 100109, Gainesville, FL, 32610, USA.
authors.forename: Kevin E
authors.initials: KE
authors.lastname: Behrns
authors.affiliation: Department of Surgery, College of Medicine, University of Florida, PO BOX 100109, Gainesville, FL, 32610, USA.
authors.forename: Lyle L
authors.initials: LL
authors.lastname: Moldawer
authors.affiliation: Department of Surgery, College of Medicine, University of Florida, PO BOX 100109, Gainesville, FL, 32610, USA.
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Thomas
authors.affiliation: Department of Pathology, Immunology, Laboratory Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: Chen
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: George
authors.affiliation: Department of Surgery, College of Medicine, University of Florida, PO BOX 100109, Gainesville, FL, 32610, USA.
authors.forename: Jose G
authors.initials: JG
authors.lastname: Trevino
authors.affiliation: Department of Oral Biology, College of Dentistry, University of Florida, PO BOX 100434, Gainesville, FL, 32610, USA. swallet@dental.ufl.edu.
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Wallet
authors.affiliation: Department of Surgery, College of Medicine, University of Florida, PO BOX 100109, Gainesville, FL, 32610, USA. steven.hughes@surgery.ufl.edu.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Hughes
mesh_terms: D056704:Adaptive Immunity / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D054357:Chemokine CXCL10 / Q000235:genetics / Q000378:metabolism; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006680:HLA Antigens / Q000235:genetics; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D007372:Interferons / Q000276:immunology*; D010190:Pancreatic Neoplasms / Q000175:diagnosis / Q000503:physiopathology*; D054367:Receptors, CXCR3 / Q000235:genetics; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment / Q000502:physiology*; D000093542:Gemcitabine
chemical_list: D054357:Chemokine CXCL10; D006680:HLA Antigens; D054367:Receptors, CXCR3; D003841:Deoxycytidine; D007371:Interferon-gamma; D007372:Interferons; D000093542:Gemcitabine
keywords: CXCL10; Epithelial cell; Immuno-oncology; Interferon-γ; Pancreatic cancer; Tumor-associated stroma