A Mechanism of Resistance to Antibody-Targeted Immune Attack.


: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+) 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.


Cancer Immunol Res


Aldeghaither DS,Zahavi DJ,Murray JC,Fertig EJ,Graham GT,Zhang YW,O'Connell A,Ma J,Jablonski SA,Weiner LM




Has Abstract


2019-02-01 00:00:00














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  • Clinical Response of a Patient to Anti-PD-1 Immunotherapy and the Immune Landscape of Testicular Germ Cell Tumors.

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    journal_title:Cancer immunology research

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    authors: Bransi A,Salgado OC,Beffinger M,Milo K,Silina K,Yagita H,Becher B,Knuth A,van den Broek M

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    journal_title:Cancer immunology research

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    authors: Siriwon N,Kim YJ,Siegler E,Chen X,Rohrs JA,Liu Y,Wang P

    更新日期:2018-07-01 00:00:00

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    journal_title:Cancer immunology research

    pub_type: 杂志文章


    authors: Du J,Lopez-Verges S,Pitcher BN,Johnson J,Jung SH,Zhou L,Hsu K,Czuczman MS,Cheson B,Kaplan L,Lanier LL,Venstrom JM

    更新日期:2014-09-01 00:00:00

  • Inhibition of SHP-1 Expands the Repertoire of Antitumor T Cells Available to Respond to Immune Checkpoint Blockade.

    abstract::The presence and activity of CD8+ T cells within the tumor microenvironment are essential for the control of tumor growth. Utilizing B16-F10 melanoma tumors that express altered peptide ligands of chicken ovalbumin, OVA257-264, we measured high- and low-affinity OVA-specific responses following adoptive transfer of OT...

    journal_title:Cancer immunology research

    pub_type: 杂志文章


    authors: Snook JP,Soedel AJ,Ekiz HA,O'Connell RM,Williams MA

    更新日期:2020-04-01 00:00:00