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Cancer Res. 2016 Mar 1;76(5):1031-43. doi: 10.1158/0008-5472.CAN-15-2001. Epub 2015 Dec 16.

Identification of the Cell-Intrinsic and -Extrinsic Pathways Downstream of EGFR and IFNγ That Induce PD-L1 Expression in Head and Neck Cancer.

Author information

1
Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania.
2
Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania.
3
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.
4
Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, Pennsylvania.
5
Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania.
6
Department of Medical Oncology, Harvard Medical School, Dana Farber Cancer Institute, Boston, Massachusetts.
7
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.

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.

PMID:
26676749
PMCID:
PMC4775348
[Available on 2017-03-01]
DOI:
10.1158/0008-5472.CAN-15-2001
[Indexed for MEDLINE]
Free PMC Article

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