32 STAT1 regulates HLA class I upregulation and immunogenicity after anti-EGFR mAb cetuximab therapy in head and neck cancer patients

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.