Evans M K, Sauer S J, Nath S, Robinson T J, Morse M A, Devi G R
Division of Surgical Sciences, Department of Surgery, Duke University Medical Center, Durham, NC, USA.
Department of Pathology, Duke University Medical Center, Durham, NC, USA.
Cell Death Dis. 2016 Jan 28;7(1):e2073. 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.
炎性乳腺癌（IBC）是最致命的一种独特的乳腺癌亚型。IBC肿瘤中表皮生长因子受体[表皮生长因子受体（EGFR）或人表皮生长因子受体2（HER2）]的高表达促使人们开展了抗EGFR/HER2单克隆抗体抑制致癌信号传导的试验；然而，原发性和获得性治疗耐药很常见。这些抗体的另一个关键功能是介导抗体依赖性细胞毒性（ADCC），使免疫效应细胞与肿瘤结合并传递颗粒酶，激活刽子手半胱天冬酶。我们假设肿瘤中抗凋亡分子的高表达会使其对ADCC产生耐药性。在此，我们证明，在IBC中过表达的最有效的半胱天冬酶抑制剂——X连锁凋亡抑制蛋白（XIAP），会导致对西妥昔单抗（抗EGFR）和曲妥珠单抗（抗HER2）介导的ADCC产生耐药。亲本IBC细胞系中XIAP的过表达增强了对ADCC的耐药性；相反，在对ADCC耐药的IBC细胞中靶向下调XIAP会使其变得敏感。正如所假设的，这种ADCC耐药部分是由于XIAP抑制半胱天冬酶活性的能力；然而，我们还意外地发现，耐药性取决于XIAP介导的、不依赖半胱天冬酶的活性氧（ROS）积累的抑制，而ROS积累在ADCC过程中原本会发生。转录组分析通过揭示XIAP过表达、对ADCC耐药的细胞中参与免疫抑制和氧化应激反应的基因的调控，支持了这些观察结果。我们得出结论，XIAP是ADCC反应性的关键调节因子，通过依赖半胱天冬酶和不依赖半胱天冬酶的机制发挥作用。这些结果表明，针对XIAP对半胱天冬酶激活和ROS抑制作用的策略有可能增强基于单克隆抗体的免疫疗法的活性。
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