EGFR y Cáncer de Cabeza y Cuello

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 EGFR_853-861-specific CTLs, and notably enhanced surface presentation of a non-EGFR peptide (MAGE-3_271-279). 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