1690P - Her Signaling Effects on the NK Cell-Mediated Cytotoxicity via Regulation of MHC Class I-Related Chain A/B in Cancer Cells

Abstract

ABSTRACT Background Overexpression of the HER receptors is associated with a poor prognosis in several types of cancer. Currently the HER receptor-targeted therapies are in clinical practice or evaluated within clinical trials, including treatment with monoclonal antibodies mediating activation of antibody induced innate or adaptive cellular immunity. A better understanding of how HER signaling in tumors influences cellular immune mechanisms is therefore warranted. We previously reported that the HER3 signaling enhanced the expression of MHC class I-related chain A and B (MICA/B), resulting in a phenotype promoting tumor escape from innate immunity. Here, we demonstrate that HER3 signaling in breast cancer (BC) cells increases MICA/B expression via AKT pathway, while EGFR signaling in non-small-cell lung cancer (NSCLC) cells decreases MICA/B expression. Material and methods A possible influence of HER signaling on MICA/B expression in BC and NSCLC cell lines was investigated. To assess the consequences of HER activation, cells were either treated with the HER3 ligand NRG or EGFR ligand EGF. NK cell-mediated cytotoxicity against tumor cells was assessed by 51Cr release assay. Results Among the major pathways activated by HER3 signaling, the PI3K-AKT pathway was shown to predominantly regulate MICA/B expression in BC cells. Treatment with NRG promoted MICA/B expression, in a process that was antagonized by pharmacological and genetic interference with HER3 but not by ATM-ATR pathway inhibitor. These observations further emphasize that HER3 signaling directly, and not via genotoxic stress, regulates MICA/B expression. In contrast, treatment with EGF decreased MICA/B expression in NSCLC cells. Among the major pathways of EGFR signaling, the MAPK pathway was shown to predominantly attenuate MICA/B expression. As expected, activation of HER3 signaling enhanced MICA/B induced NK cell cytotoxicity, while activation of EGFR signaling attenuated it. Conclusions We conclude that HER signaling directly regulates the expression of MICA/B and that this may influence the recognition of tumor cells by the innate immune system. Disclosure All authors have declared no conflicts of interest.