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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    pub_type: 杂志文章


    authors: Chu Y,Hochberg J,Yahr A,Ayello J,van de Ven C,Barth M,Czuczman M,Cairo MS

    更新日期:2015-04-01 00:00:00

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    pub_type: 杂志文章


    authors: Parihar R,Rivas C,Huynh M,Omer B,Lapteva N,Metelitsa LS,Gottschalk SM,Rooney CM

    更新日期:2019-03-01 00:00:00

  • Pathogen-driven cancers and emerging immune therapeutic strategies.

    abstract::Infectious agents play an etiologic role in approximately 20% of cancer cases worldwide. Eleven pathogens (seven viruses, three parasites, and one bacterium) are known to contribute to oncogenesis either directly via the expression of their protein products or indirectly via chronic inflammation. Although prevention o...

    journal_title:Cancer immunology research

    pub_type: 杂志文章,评审


    authors: Vandeven N,Nghiem P

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  • YAP-Induced PD-L1 Expression Drives Immune Evasion in BRAFi-Resistant Melanoma.

    abstract::Activation of YAP, a Hippo pathway effector, is an important resistance mechanism to BRAF inhibitor (BRAFi) in melanoma. Emerging evidence also suggests that YAP is involved in suppression of the antitumor immune response. However, the potential direct impact of YAP activity on cytotoxic T-cell immune responses has no...

    journal_title:Cancer immunology research

    pub_type: 杂志文章


    authors: Kim MH,Kim CG,Kim SK,Shin SJ,Choe EA,Park SH,Shin EC,Kim J

    更新日期:2018-03-01 00:00:00