STAT1-Induced HLA Class I Upregulation Enhances Immunogenicity and Clinical Response to Anti-EGFR mAb Cetuximab Therapy in HNC Patients.

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.

journal_name

Cancer Immunol Res

authors

Srivastava RM,Trivedi S,Concha-Benavente F,Hyun-Bae J,Wang L,Seethala RR,Branstetter BF 4th,Ferrone S,Ferris RL

doi

10.1158/2326-6066.CIR-15-0053

subject

Has Abstract

pub_date

2015-08-01 00:00:00

pages

936-45

issue

8

eissn

2326-6066

issn

2326-6074

pii

2326-6066.CIR-15-0053

journal_volume

3

pub_type

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