title: Inactivation of Interferon Receptor Promotes the Establishment of Immune Privileged Tumor Microenvironment.
abstract: Refractoriness of solid tumors, including colorectal cancers (CRCs), to immunotherapies is attributed to the immunosuppressive tumor microenvironment that protects malignant cells from cytotoxic T lymphocytes (CTLs). We found that downregulation of the type I interferon receptor chain IFNAR1 occurs in human CRC and mouse models of CRC. Downregulation of IFNAR1 in tumor stroma stimulated CRC development and growth, played a key role in formation of the immune-privileged niche, and predicted poor prognosis in human CRC patients. Genetic stabilization of IFNAR1 improved CTL survival and increased the efficacy of the chimeric antigen receptor T cell transfer and PD-1 inhibition. Likewise, pharmacologic stabilization of IFNAR1 suppressed tumor growth providing the rationale for upregulating IFNAR1 to improve anti-cancer therapies.
authors.affiliation: Department of Biomedical Sciences, Mari Lowe Center for Comparative Oncology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Kanstantsin V
authors.initials: KV
authors.lastname: Katlinski
authors.affiliation: Department of Biomedical Sciences, Mari Lowe Center for Comparative Oncology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Gui
authors.affiliation: Department of Biomedical Sciences, Mari Lowe Center for Comparative Oncology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Yuliya V
authors.initials: YV
authors.lastname: Katlinskaya
authors.affiliation: Department of Biomedical Sciences, Mari Lowe Center for Comparative Oncology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Angelíca
authors.initials: A
authors.lastname: Ortiz
authors.affiliation: Department of Biomedical Sciences, Mari Lowe Center for Comparative Oncology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Riddhita
authors.initials: R
authors.lastname: Chakraborty
authors.affiliation: Department of Biomedical Sciences, Mari Lowe Center for Comparative Oncology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Sabyasachi
authors.initials: S
authors.lastname: Bhattacharya
authors.affiliation: Department of Biomedical Sciences, Mari Lowe Center for Comparative Oncology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Carbone
authors.affiliation: Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Beiting
authors.affiliation: Department of Pathology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Melanie A
authors.initials: MA
authors.lastname: Girondo
authors.affiliation: Department of Pathology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Amy R
authors.initials: AR
authors.lastname: Peck
authors.affiliation: Department of Biomedical Sciences, Mari Lowe Center for Comparative Oncology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Ellen
authors.initials: E
authors.lastname: Puré
authors.affiliation: Division of Gastroenterology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Priya
authors.initials: P
authors.lastname: Chatterji
authors.affiliation: Division of Gastroenterology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Rustgi
authors.affiliation: Department of Biochemistry, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: J Alan
authors.initials: JA
authors.lastname: Diehl
authors.affiliation: Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Constantinos
authors.initials: C
authors.lastname: Koumenis
authors.affiliation: Department of Pathology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Hallgeir
authors.initials: H
authors.lastname: Rui
authors.affiliation: Department of Biomedical Sciences, Mari Lowe Center for Comparative Oncology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: syfuchs@upenn.edu.
authors.forename: Serge Y
authors.initials: SY
authors.lastname: Fuchs
mesh_terms: D000818:Animals; D002470:Cell Survival; D015179:Colorectal Neoplasms / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D015536:Down-Regulation; D006801:Humans; D007108:Immune Tolerance; D051379:Mice; D008810:Mice, Inbred C57BL; D053633:Receptor, Interferon alpha-beta / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D013602:T-Lymphocytes, Cytotoxic / Q000502:physiology; D059016:Tumor Microenvironment
chemical_list: C507964:IFNAR1 protein, human; D053633:Receptor, Interferon alpha-beta
keywords: IFNAR1; colorectal cancer; cytotoxic T cells; immunosuppression; interferon; receptor; tumor microenvironment