X-linked inhibitor of apoptosis protein mediates tumor cell resistance to antibody-dependent cellular cytotoxicity.
Abstract
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.
Type
Journal articleSubject
Antibody-Dependent Cell CytotoxicityApoptosis
Cell Line, Tumor
Cetuximab
Drug Resistance, Neoplasm
Female
Gene Knockdown Techniques
Humans
Immunotherapy
Inflammatory Breast Neoplasms
Killer Cells, Natural
NF-kappa B
Reactive Oxygen Species
Receptor, ErbB-2
Trastuzumab
X-Linked Inhibitor of Apoptosis Protein
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https://hdl.handle.net/10161/12402Published Version (Please cite this version)
10.1038/cddis.2015.412Publication Info
Evans, MK; Sauer, SJ; Nath, S; Robinson, TJ; Morse, MA; & Devi, GR (2016). X-linked inhibitor of apoptosis protein mediates tumor cell resistance to antibody-dependent
cellular cytotoxicity. Cell Death Dis, 7. pp. e2073. 10.1038/cddis.2015.412. Retrieved from https://hdl.handle.net/10161/12402.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Gayathri R. Devi
Associate Professor in Surgery
Dr. Devi’s research interests include functional genomics, anti-cancer drug
discovery and development, mechanisms of cancer cell signaling, tumor immunity and
applications thereof for overcoming therapeutic resistance in cancer. The lab has
established prostate, inflammatory breast cancer and ovarian cellular and tumor models.
Michael Aaron Morse
Professor of Medicine
We are studying the use of immune therapies to treat various cancers, including gastrointestinal,
breast, and lung cancers and melanoma. These therapies include vaccines based on
dendritic cells developed in our laboratory as well as vaccines based on peptides,
viral vectors, and DNA plasmids. Our group is also a national leader in the development
and use of laboratory assays for demonstrating immunologic responses to cancer vaccines.
Finally, we are developing immunotherapies based on ado
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