TY - JOUR
T1 - A mechanism of resistance to antibody-targeted immune attack
AU - Aldeghaither, Dalal S.
AU - Zahavi, David J.
AU - Murray, Joseph C.
AU - Fertig, Elana J.
AU - Graham, Garrett T.
AU - Zhang, Yong Wei
AU - O'Connell, Allison
AU - Ma, Junfeng
AU - Jablonski, Sandra A.
AU - Weiner, Louis M.
N1 - Funding Information:
D.S. Aldeghaither was supported by a scholarship from the Government of Saudi Arabia and King Saud bin Abdulaziz University for Health Sciences. J.C. Murray was supported by anindividual pre-doctoralNRSA fellowship, NCI F30-CA165474. L.M. Weiner was supported by NCI grants R01 CA050633 and P30 CA051008. The Tissue Culture, Proteomics and Metabolomics, Flow Cytometry and Cell Sorting, Genomics and Epigenomics, and Microscopy and Imaging Shared Resources were supported by the Lombardi Comprehensive Cancer Center Support Grant NCI P30-CA051008. E.J. Fertig was supported by NCI R01 CA177669, P30 CA006973, and the Johns Hopkins University Award.
Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2019/2
Y1 - 2019/2
N2 - Targeted monoclonal antibody therapy is a promising therapeutic strategy for cancer, and antibody-dependent cell-mediated cytotoxicity (ADCC) represents a crucial mechanism underlying these approaches. The majority of patients have limited responses to monoclonal antibody therapy due to the development of resistance. Models of ADCC provide a system for uncovering immune-resistance mechanisms. We continuously exposed epidermal growth factor receptor (EGFR þ ) A431 cells to KIR-deficient NK92-CD16V effector cells and the anti-EGFR cetuximab. Persistent ADCC exposure yielded ADCC-resistant cells (ADCCR1) that, compared with control ADCC-sensitive cells (ADCCS1), exhibited reduced EGFR expression, overexpression of histone- and interferon-related genes, and a failure to activate NK cells, without evidence of epithelial-to-mesenchymal transition. These properties gradually reversed following withdrawal of ADCC selection pressure. The development of resistance was associated with lower expression of multiple cell-surface molecules that contribute to cell-cell interactions and immune synapse formation. Classic immune checkpoints did not modulate ADCC in this unique model system of immune resistance. We showed that the induction of ADCC resistance involves genetic and epigenetic changes that lead to a general loss of target cell adhesion properties that are required for the establishment of an immune synapse, killer cell activation, and target cell cytotoxicity.
AB - Targeted monoclonal antibody therapy is a promising therapeutic strategy for cancer, and antibody-dependent cell-mediated cytotoxicity (ADCC) represents a crucial mechanism underlying these approaches. The majority of patients have limited responses to monoclonal antibody therapy due to the development of resistance. Models of ADCC provide a system for uncovering immune-resistance mechanisms. We continuously exposed epidermal growth factor receptor (EGFR þ ) A431 cells to KIR-deficient NK92-CD16V effector cells and the anti-EGFR cetuximab. Persistent ADCC exposure yielded ADCC-resistant cells (ADCCR1) that, compared with control ADCC-sensitive cells (ADCCS1), exhibited reduced EGFR expression, overexpression of histone- and interferon-related genes, and a failure to activate NK cells, without evidence of epithelial-to-mesenchymal transition. These properties gradually reversed following withdrawal of ADCC selection pressure. The development of resistance was associated with lower expression of multiple cell-surface molecules that contribute to cell-cell interactions and immune synapse formation. Classic immune checkpoints did not modulate ADCC in this unique model system of immune resistance. We showed that the induction of ADCC resistance involves genetic and epigenetic changes that lead to a general loss of target cell adhesion properties that are required for the establishment of an immune synapse, killer cell activation, and target cell cytotoxicity.
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U2 - 10.1158/2326-6066.CIR-18-0266
DO - 10.1158/2326-6066.CIR-18-0266
M3 - Article
C2 - 30563830
AN - SCOPUS:85060932596
SN - 2326-6066
VL - 7
SP - 230
EP - 243
JO - Cancer Immunology Research
JF - Cancer Immunology Research
IS - 2
ER -