X-linked inhibitor of apoptosis protein mediates tumor cell resistance to antibody-dependent cellular cytotoxicity

• Published in: Cell death & disease Vol. 7; no. 1; p. e2073
• Main Authors: Evans, M K, Sauer, S J, Nath, S, Robinson, T J, Morse, M A, Devi, G R
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.01.2016; Springer Nature B.V; Nature Publishing Group
• Subjects: 13/1; 13/2; 13/31; 14/63; 45/61; 631/80/82/23; 631/80/86; 692/699/67/1059/2325; 692/699/67/1347; 82/80; 96/109; Antibodies; Antibody-Dependent Cell Cytotoxicity - drug effects; Apoptosis; Apoptosis - drug effects; Apoptosis - immunology; Biochemistry; Biomedical and Life Sciences; Breast cancer; Cell Biology; Cell Culture; Cell Line, Tumor; Cetuximab - pharmacology; Cytotoxicity; Drug Resistance, Neoplasm; Female; Gene Knockdown Techniques; Humans; Immunoglobulins; Immunology; Immunotherapy - methods; Inflammatory Breast Neoplasms - genetics; Inflammatory Breast Neoplasms - immunology; Inflammatory Breast Neoplasms - pathology; Inflammatory Breast Neoplasms - therapy; Killer Cells, Natural - drug effects; Killer Cells, Natural - immunology; Life Sciences; NF-kappa B - metabolism; Original; original-article; Protein expression; Reactive Oxygen Species - metabolism; Receptor, ErbB-2 - biosynthesis; Trastuzumab - pharmacology; X-Linked Inhibitor of Apoptosis Protein - deficiency; X-Linked Inhibitor of Apoptosis Protein - genetics; X-Linked Inhibitor of Apoptosis Protein - immunology
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2015.412

Inflammatory breast cancer (IBC) is the deadliest, distinct subtype of breast cancer. High expression of epidermal growth factor receptors [EGFR or human epidermal growth factor receptor 2 (HER2)] in IBC tumors has prompted trials of anti-EGFR/HER2 monoclonal antibodies to inhibit oncogenic signaling; however, de novo and acquired therapeutic resistance is common. Another critical function of these antibodies is to mediate antibody-dependent cellular cytotoxicity (ADCC), which enables immune effector cells to engage tumors and deliver granzymes, activating executioner caspases. We hypothesized that high expression of anti-apoptotic molecules in tumors would render them resistant to ADCC. Herein, we demonstrate that the most potent caspase inhibitor, X-linked inhibitor of apoptosis protein (XIAP), overexpressed in IBC, drives resistance to ADCC mediated by cetuximab (anti-EGFR) and trastuzumab (anti-HER2). Overexpression of XIAP in parental IBC cell lines enhances resistance to ADCC; conversely, targeted downregulation of XIAP in ADCC-resistant IBC cells renders them sensitive. As hypothesized, this ADCC resistance is in part a result of the ability of XIAP to inhibit caspase activity; however, we also unexpectedly found that resistance was dependent on XIAP-mediated, caspase-independent suppression of reactive oxygen species (ROS) accumulation, which otherwise occurs during ADCC. Transcriptome analysis supported these observations by revealing modulation of genes involved in immunosuppression and oxidative stress response in XIAP-overexpressing, ADCC-resistant cells. We conclude that XIAP is a critical modulator of ADCC responsiveness, operating through both caspase-dependent and -independent mechanisms. These results suggest that strategies targeting the effects of XIAP on caspase activation and ROS suppression have the potential to enhance the activity of monoclonal antibody-based immunotherapy.