Identification of the Cell-Intrinsic and -Extrinsic
Pathways Downstream of EGFR and IFNγ That Induce PD-L1 Expression in Head and
Neck Cancer.
Concha-Benavente F1,
Srivastava RM2, Trivedi S2, Lei Y3, Chandran U4, Seethala RR5, Freeman
GJ6, Ferris RL7.
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.
Cancer Res. 2016 Mar
1;76(5):1031-43. doi: 10.1158/0008-5472.CAN-15-2001. Epub 2015 Dec 16.
Md. PhD. Fernando Concha. Ex-miembro del GII
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