STAT1-Induced HLA Class I Upregulation Enhances Immunogenicity and Clinical Response to Anti-EGFR mAb Cetuximab Therapy in HNC Patients.
Srivastava RM1, Trivedi S1, Concha-Benavente F2, Hyun-Bae J1, Wang L1, Seethala RR3, Branstetter BF 4th4, Ferrone S5, Ferris RL6.
1Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania.
2Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania.
3Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania.
4Department of Radiology, University of Pittsburgh, Pittsburgh, Pennsylvania.
5Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
6Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania. Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania. Cancer Immunology Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania. ferrisrl@upmc.edu.
Abstract
The
goal of this study was to characterize the molecular mechanisms
underlying cetuximab-mediated upregulation of HLA class I
antigen-processing machinery components in head and neck cancer (HNC)
cells and to determine the clinical significance of these changes in
cetuximab-treated HNC patients. Flow cytometry, signaling studies, and
chromatin immunoprecipitation (ChIP) assays were performed using HNC
cells treated with cetuximab alone or with Fcγ receptor (FcγR)-bearing
lymphocytes to establish the mechanism of EGFR-dependent regulation of
HLA APM expression. A prospective phase II clinical trial of neoadjuvant
cetuximab was used to correlate HLA class I expression with clinical
response in HNC patients. EGFR blockade triggered STAT1 activation and
HLA upregulation, in a src homology-containing protein (SHP)-2-dependent
fashion, more prominently in HLA-B/C than in HLA-A alleles. EGFR
signaling blockade also enhanced IFNγ receptor 1 (IFNAR) expression,
augmenting induction of HLA class I and TAP1/2 expression by IFNγ, which
was abrogated in STAT1-/- cells. Cetuximab enhanced HNC cell recognition by EGFR853-861-specific CTLs, and notably enhanced surface presentation of a non-EGFR peptide (MAGE-3271-279).
HLA class I upregulation was significantly associated with clinical
response in cetuximab-treated HNC patients. EGFR induces HLA
downregulation through SHP-2/STAT1 suppression. Reversal of HLA class I
downregulation was more prominent in clinical responders to cetuximab
therapy, supporting an important role for adaptive immunity in cetuximab
antitumor activity. Abrogating EGFR-induced immune escape mechanisms
and restoring STAT1 signaling to reverse HLA downregulation using
cetuximab should be combined with strategies to enhance adaptive
cellular immunity. Cancer Immunol Res; 3(8); 1-10. ©2015 AACR.
©2015 American Association for Cancer Research.
Cancer Immunol Res. 2015 May 13. [Epub ahead of print]
http://cancerimmunolres.aacrjournals.org/content/early/2015/07/08/2326-6066.CIR-15-0053.abstract?sid=417db2a5-a149-461c-a080-8c3722e523a3
Md. PhD. Fernando Concha. Ex-miembro del GII