title: Identification of the Cell-Intrinsic and -Extrinsic Pathways Downstream of EGFR and IFNγ That Induce PD-L1 Expression in Head and Neck Cancer.
abstract: Many cancer types, including head and neck cancers (HNC), express programmed death ligand 1 (PD-L1). Interaction between PD-L1 and its receptor, programmed death 1 (PD-1), inhibits the function of activated T cells and results in an immunosuppressive microenvironment, but the stimuli that induce PD-L1 expression are not well characterized. Interferon gamma (IFNγ) and the epidermal growth factor receptor (EGFR) utilize Janus kinase 2 (JAK2) as a common signaling node to transmit tumor cell-mediated extrinsic or intrinsic signals, respectively. In this study, we investigated the mechanism by which these factors upregulate PD-L1 expression in HNC cells in the context of JAK/STAT pathway activation, Th1 inflammation, and HPV status. We found that wild-type, overexpressed EGFR significantly correlated with JAK2 and PD-L1 expression in a large cohort of HNC specimens. Furthermore, PD-L1 expression was induced in an EGFR- and JAK2/STAT1-dependent manner, and specific JAK2 inhibition prevented PD-L1 upregulation in tumor cells and enhanced their immunogenicity. Collectively, our findings suggest a novel role for JAK2/STAT1 in EGFR-mediated immune evasion, and therapies targeting this signaling axis may be beneficial to block PD-L1 upregulation found in a large subset of HNC tumors.
authors.affiliation: Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Fernando
authors.initials: F
authors.lastname: Concha-Benavente
authors.affiliation: Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Raghvendra M
authors.initials: RM
authors.lastname: Srivastava
authors.affiliation: Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Sumita
authors.initials: S
authors.lastname: Trivedi
authors.affiliation: Department of Periodontics and Oral Medicine, School of Dentistry and Department of Otolaryngology-Head and Neck Surgery, School of Medicine. University of Michigan, Ann Arbor, Michigan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Lei
authors.affiliation: Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Uma
authors.initials: U
authors.lastname: Chandran
authors.affiliation: Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Raja R
authors.initials: RR
authors.lastname: Seethala
authors.affiliation: Department of Medical Oncology, Harvard Medical School, Dana Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Freeman
authors.affiliation: Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania. Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania. Cancer Immunology Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania. ferrisrl@upmc.edu.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Ferris
mesh_terms: D060890:B7-H1 Antigen / Q000032:analysis / Q000502:physiology*; D045744:Cell Line, Tumor; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000502:physiology*; D006258:Head and Neck Neoplasms / Q000276:immunology* / Q000821:virology; D006801:Humans; D007371:Interferon-gamma / Q000502:physiology*; D053614:Janus Kinase 2 / Q000502:physiology*; D007694:Killer Cells, Natural / Q000276:immunology; D027383:Papillomaviridae / Q000302:isolation & purification; D050794:STAT1 Transcription Factor / Q000502:physiology*
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D004815:Epidermal Growth Factor; D007371:Interferon-gamma; C512478:EGFR protein, human; D066246:ErbB Receptors; C507924:JAK2 protein, human; D053614:Janus Kinase 2