Epidermal Growth Factor Receptor Inhibition Augments the Expression of MHC Class I and II Genes

Purpose: Diverse immune-related effects occur with the use of epidermal growth factor receptor inhibitors (EGFRI). In addition to the cutaneous inflammation induced by EGFRIs, these agents have been associated with the exacerbation of autoimmune skin disease and contact hypersensitivity, antiviral effects, and fatal alveolar damage in the setting of lung transplantation. Because EGFR ligands can modulate MHC class I (MHCI) and II (MHCII) molecule expression, we hypothesized that some of the immune-related effects of EGFRIs are due to direct effects on the expression of MHCI and/or MHCII molecules. Experimental Design: Primary human keratinocytes and a malignant keratinocyte cell line (A431) were treated with EGFRIs alone or prior to IFN-gamma, a potent inducer of MHCI and MHCII molecule expression. CIITA, MHCI, and MHCII RNA expression was measured using quantitative real-time reverse transcriptase PCR, and cell surface MHCI and MHCII protein expression was measured using flow cytometry. Skin biopsies from patients were analyzed for MHCI and MHCII protein expression before and during therapy with an EGFRI using immunohistochemistry. Results: Both EGFR tyrosine kinase inhibitors and ligand-blocking antibodies (cetuximab) augmented the induction of MHCI and MHCII molecules by IFN-gamma in primary and malignant human keratinocytes. Unexpectedly, the increase in MHCI protein expression did not require the presence of IFN-gamma. Consistent with these in vitro findings, skin biopsies from cancer patients exhibited increased epidermal MHCI protein expression during therapy with an EGFRI as well as increases in MHCI and MHCII molecule RNA. Conclusions: These studies suggest that EGFRIs may influence immune/inflammatory responses by directly modulating MHC expression. Clin Cancer Res; 17(13); 4400-13. (C) 2011 AACR.