Immune biomarkers of anti-EGFR monoclonal antibody therapy

Abstract

The tumor antigen (TA)-targeted monoclonal antibodies (mAb) cetuximab and panitumumab target the human epidermal growth factor receptor and have been integrated into treatment regimens for advanced squamous cell carcinoma of the head and neck (SCCHN). The therapeutic efficacy of these mAbs has been found to be enhanced when combined with radiotherapy and chemotherapy. However, clinical trials indicate that these findings are limited to fewer than 20% of treated patients. Therefore, identifying patients who are likely to benefit from these agents is crucial to improving therapeutic strategies. Interestingly, it has been noted that TA-targeted mAbs mediate their effects by contributing to cell-mediated cytotoxicity in addition to inhibition of downstream signaling pathways. Here, we describe the potential immunogenic mechanisms underlying these clinical findings, their role in the varied clinical response and identify the putative biomarkers of antitumor activity. We review potential immunological biomarkers that affect mAb therapy in SCCHN patients, the implications of these findings and how they translate to the clinical scenario, which are critical to improving patient selection and ultimately outcomes for patients undergoing therapy.

Keywords: EGFR; head and neck cancer; immune biomarkers; monoclonal antibodies.

Figure 1.

Antibody-dependent, cell-mediated cytotoxicity (ADCC). ADCC mediated by tumor antigen (TA)-targeted monoclonal antibodies (mAbs) in the tumor microenvironment. TA-positive tumor cells are exposed to TA-targeted mAbs which leads to opsonization through binding of cetuximab and panitumumab to the TA epitopes expressed on tumor targets. NK cell recognition of opsonized tumor cells is mediated via Fcgamma receptor (FcγR) III/CD16 while FcγRIIa/CD32 mediates recognition. This effect is diminished by regulatory T cells (Treg) which exert a suppressive function on effector immune cells through secretion of interleukin 10, transforming growth factor-β and adenosine into the tumor microenvironment.

Figure 2.

Signal transducer and activator of transcription 3 (STAT3) pathways involved in immune escape. epidermal growth factor receptor (EGFR) overexpression noted in squamous cell carcinoma of the head and neck results in constitutive STAT3 activation through the JAK/STAT pathway. STAT3 is a known oncogenic transcription factor which results in tumor growth and immune suppression, in part due to the induction of immunosuppressive cytokines such as interleukin 6 (IL-6), vascular endothelial growth factor (VEGF) and interleukin 10 (IL-10). The IL-6R/CD130 signaling complex, also upregulated in squamous cell carcinoma of the head and neck, is a major pathway in EGFR-independent STAT3 activation and may contribute to the modest response seen in therapy with EGFR-blocking antibodies. Interferon-γ (IFN-γ) activates STAT1 phosphorylation which opposes the action of STAT3, EGFR overexpression activates SHP2 which conversely inhibits the phosphorylation of STAT1.