114 - Interleukin-1 Signaling is Required for HNSCC Tumor Response to Cetuximab

Abstract

Despite the incorporation of the epidermal growth factor receptor (EGFR) inhibitor cetuximab into the clinical management of head and neck squamous cell carcinoma (HNSCC), limited to no long-term changes in overall survival are observed in HNSCC patients even though EGFR is expressed at high levels in these tumors. Therefore, the identification of novel therapeutic approaches to enhance the clinical efficacy of cetuximab could lead to improved long-term survival for HNSCC patients. Our previous work indicated that cetuximab triggers the release of pro-inflammatory cytokines directly from HNSCC tumor cells, which was mediated by interleukin-1 (IL-1) signaling. The IL-1 pathway plays a central role in immune response by regulating the expression of various inflammatory genes in immune cells. IL-1 signaling is also involved in antitumor immunity specifically via natural killer (NK)-cell mediated antibody-dependent cell-mediated cytotoxicity (ADCC), which is believed to be the major mechanism of action of cetuximab. Therefore we propose that IL-1 signaling is required for HNSCC tumor response to cetuximab. We found that blockade of IL-1 signaling using an IL-1-receptor antagonist (IL-1RA, anakinra) suppressed the anti-tumor efficacy of cetuximab, while IL-1 alpha (IL-1α) overexpression enhanced HNSCC tumor response to cetuximab in SQ20B xenograft mouse models. Blockade of IL-1 signaling also suppressed cetuximab-induced NK-cell-mediated ADCC by a mechanism involving decreased inducible nitric oxide synthase (iNOS) activity. These results support the idea that IL-1 signaling is necessary for HNSCC tumor response to cetuximab and that iNOS activity may be an important mediator in the mechanism of action of IL-1 signaling.