32 STAT1 regulates HLA class I upregulation and immunogenicity after anti-EGFR mAb cetuximab therapy in head and neck cancer patients. Issue 5 (May 2015)

• Record Type: Journal Article
• Authors: Trivedi, S.; Wang, L.; Sheethala, R.R.; Ferrone, S.; Branstetter, B.F.; Ferris, R.L.
• Is Part Of: Oral oncology. Volume 51:Issue 5(2015:May)
• Page Start: e37
• Publication Date: 2015-05
• Subjects: Mouth -- Cancer -- Periodicals; Mouth -- Tumors -- Periodicals; Mouth Diseases -- Periodicals; Mouth Neoplasms -- Periodicals; Bouche -- Cancer -- Périodiques; Bouche -- Tumeurs -- Périodiques; Tumeurs -- Périodiques; Electronic journals; 616.9943105
• DOI: 10.1016/j.oraloncology.2015.02.033
• Languages: English
• ISSNs: 1368-8375

Abstract

Abstract : Purpose: Head and neck cancer (HNC) cells express low HLA class I antigen processing machinery (APM) components, providing a major immune escape strategy from cytotoxic T lymphocyte (CTL)-mediated lysis. Epidermal growth factor receptor (EGFR)-specific CTL are induced by the therapeutic mAb cetuximab in treated patients. Therefore, the effect and molecular mechanism of EGFR inhibition on HLA class I APM expression has important implications for adaptive immunity generated in cetuximab-treated HNC patients. Experimental design: Using a prospective clinical trial of neoadjuvant, single-agent cetuximab, we correlated immunohistochemistry (IHC) results with clinical response. Flow cytometry and signaling studies were performed using HNC lines treated with cetuximab alone or with Fc γ receptor (Fc γ R) bearing lymphocytes to establish the mechanism of EGFR-dependent regulation of HLA APM expression. Results: Cetuximab-mediated EGFR blockade triggered STAT1 activation and upregulation of HLA-B/C alleles more prominently than HLA-A alleles. Cetuximab-induced HLA class I upregulation was most prominent in cetuximab-treated HNC patients with beneficial clinical response to cetuximab. EGFR signaling blockade enhanced IFN γ receptor 1 (IFNAR) on HNC, and augmented induction of HLA class I and TAP1/2 expression by IFN γ which was abrogated in STAT1−/− cells. In addition, cetuximab treatment enhanced the HNC cell recognition by EGFR853-861 specific CTL and also enhanced surface presentation of non-EGFR TA such as MAGE-3271-279. Conclusions: HLA class I induction is a favorable biomarker for cetuximab therapy. EGFR signaling mediates a novel immune escape mechanism through STAT1 suppression. Reversal of HLA downregulation using cetuximab should be combined with strategies to enhance adaptive cellular immunity.