Concha-Benavente, Fernando
(2016)
Epidermal growth factor receptor and Janus Kinase 2 regulation of programmed death ligand 1 and immunoescape in head and neck cancer.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Co-inhibitory immune checkpoint receptors (ICR) are novel targets for cancer immunotherapy. Programmed death ligand 1 (PD-L1), expressed in many cancers, including head and neck cancers (HNC), interacts with its receptor, programmed death 1 (PD-1), resulting in an exhausted phenotype. As yet, the stimuli and pathways that induce PD-L1 expression in tumor cells are not fully understood. Interferon gamma (IFNγ) and the epidermal growth factor receptor (EGFR) utilize Janus kinase 2 (JAK2) as a common signaling node transmitting tumor cell-mediated extrinsic or intrinsic signals, respectively. We investigated the mechanisms by which these factors upregulate PD-L1 and immunosuppressive cytokine expression in HNC cells in the context of EGFR/JAK/STAT pathway activation. We found that wild type overexpressed EGFR significantly correlated with JAK2 and PD-L1 expression. Furthermore, PD-L1 expression was induced in an EGFR- and JAK2-dependent manner, and specific JAK2 inhibition prevented PD-L1 upregulation in HNC, enhancing their immunogenicity. HNC tumors have higher expression of immunosuppressive cytokines including TGFβ, IL-10, VEGF-A and IDO and lower expression of inflammatory cytokines such as IL-12A and IL-17A than controls. EGFR/JAK2 inhibition downregulated secretion of these STAT3-dependent cytokines in vitro, suggesting that targeting the EGFR/JAK2/STAT3 suppressive pathway may reverse tumor immunoescape. This view is supported by in vivo findings where HNC patients unresponsive to cetuximab therapy had significantly higher concentrations of immunosuppressive cytokines.
NK cells are crucial for promoting T cell responses against cancer. However, NK cell PD-1 expression remains largely undefined. Cetuximab-activated NK cells constitute the major effector cell subset that lyses tumor targets via antibody dependent cellular cytotoxicity (ADCC). We demonstrate that expression of PD-1 in HNC tumors correlates with NK cell activation markers. HNC patients exhibit higher levels of circulating PD-1+ NK cells, which are further enriched in the tumor. Interestingly, cetuximab treatment increased this frequency in vitro and in vivo. Inhibition of the PD-L1/PD-1 axis increased cetuximab-mediated NK cell activation and cytotoxicity.
Collectively, our findings suggest a novel role for JAK2 in EGFR-mediated PD-L1 upregulation and immunosuppressive cytokine secretion. Importantly, combined inhibition of the EGFR and PD-L1/PD-1 axis presents a potential strategy to reverse cetuximab-resistant immune evasion of HNC by enhancing NK cell cytotoxicity.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
| Creators | Email | Pitt Username | ORCID  |
|---|
| Concha-Benavente, Fernando | fbc4@pitt.edu | FBC4 | |
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| ETD Committee: |
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| Date: |
20 May 2016 |
| Date Type: |
Publication |
| Defense Date: |
16 March 2016 |
| Approval Date: |
20 May 2016 |
| Submission Date: |
30 March 2016 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
173 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Immunology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
EGFR, PD-L1, PD-1, NK cell, immunoescape |
| Date Deposited: |
20 May 2016 15:11 |
| Last Modified: |
19 Dec 2016 14:43 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/27431 |
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