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

Abstract

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-g, 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-g in primary and malignant human keratinocytes. Unexpectedly, the increase in MHCI protein expression did not require the presence of IFN-g. 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. Ó2011 AACR.

NLRC5/MHC class I transactivator is a target for immune evasion in cancer

“…Therapeutics augmenting NLRC5 activity could compensate for this deficit by breaking cancer immune evasion in a broad range of tumor types. Interestingly, it has been reported that currently used therapies, such as an EGF receptor inhibitor (cetuximab) or a B-Raf inhibitor (vemurafenib), enhance MHC class I expression via IFN-γ (35,36). Therefore, these currently available therapies, originally designed to disrupt oncogenic signaling, may mediate their effects in part via the NLRC5-dependent MHC class I pathway.…”

Radiotherapy plus EGFR inhibitors: synergistic modalities

“…If this were the case, the blockade of both targets might constitute a new therapeutic strategy [66]. Moreover, as shown by Pollack et al, EGFR-blockers may overcome the inhibitory effect of EGFR-signalling by increasing MHC expression [67]. We thus also suggest that the overall efficacy of EGFR inhibitor-targeted therapy in SCCHN patients could be enhanced by the addition of T-cell-based immunotherapy.…”

High Expression of Major Histocompatibility Complex Class I in Clear Cell Renal Cell Carcinoma Is Associated with Improved Prognosis

“…Conversely, tumors with decreased MHCI expression may be able to escape immune recognition and metastasize, eventually leading to patient death. Indeed, recent studies suggest that some canonical oncogenic signal transduction pathways that regulate tumor cell growth also influence the expression genes that govern immune recognition and escape, such as MHCI molecules [13,19]. In support of this notion, Luboldt et al [20] found that a specific MHCI haplotype, HLA-A1, was lost in the tumors of patients with advanced renal cancer, but that HLA-A1 was expressed highly in these patients' peripheral blood lymphocytes and normal renal parenchyma.…”

“…After staining, whole-slide scanning and automated image analysis was used to quantify the strength of the IHC MHCI staining, using techniques we have previously published with modifications [13]. Five representative tumor areas (2,500 × 2,500 pixels) were selected and averaged using the positive pixel count (PPC) algorithm of the Aperio image analysis software (PPC version 9, online suppl.…”