2015
DOI: 10.18632/oncotarget.6353
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Taxanes enhance trastuzumab-mediated ADCC on tumor cells through NKG2D-mediated NK cell recognition

Abstract: Recent clinical data indicate a synergistic therapeutic effect between trastuzumab and taxanes in neoadjuvantly treated HER2-positive breast cancer (BC) patients. In HER2+ BC experimental models and patients, we investigated whether this synergy depends on the ability of drug-induced stress to improve NK cell effectiveness and thus trastuzumab-mediated ADCC. HER2+ BC cell lines BT474 and MDAMB361 treated with docetaxel showed up-modulation of NK activator ligands both in vitro and in vivo, accompanied by a 15–… Show more

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Cited by 41 publications
(29 citation statements)
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“…Consistently, it has been reported that patient response to trastuzumab monotherapy is associated with robust tumor infiltration of lymphoid cells [ 18 ]—primarily NK cells [ 19 ]—and a greater capacity of NK cells to mediate in vitro antibody-dependent cellular cytotoxicity [ 20 , 21 ]. We recently demonstrated the involvement of NKG2D in the induction of trastuzumab-mediated ADCC by NK cells [ 21 ], which could explain the synergism between trastuzumab and taxanes in clinical trials [ 22 ]—NKG2D expression on NK cells is increased by taxanes and is associated with NK cytotoxic activity [ 21 ]. Moreover, NKG2D receptor on NK cells binds to MICA, one of its ligands, on monocytes that reside in the tumor microenvironment, boosting NK cell antitumor activity against Ab-coated tumor cells and ultimately increasing their production of interferon- γ (IFN γ ) [ 23 ].…”
Section: Mechanisms Of Action Of Her2-targeting Agentsmentioning
confidence: 79%
“…Consistently, it has been reported that patient response to trastuzumab monotherapy is associated with robust tumor infiltration of lymphoid cells [ 18 ]—primarily NK cells [ 19 ]—and a greater capacity of NK cells to mediate in vitro antibody-dependent cellular cytotoxicity [ 20 , 21 ]. We recently demonstrated the involvement of NKG2D in the induction of trastuzumab-mediated ADCC by NK cells [ 21 ], which could explain the synergism between trastuzumab and taxanes in clinical trials [ 22 ]—NKG2D expression on NK cells is increased by taxanes and is associated with NK cytotoxic activity [ 21 ]. Moreover, NKG2D receptor on NK cells binds to MICA, one of its ligands, on monocytes that reside in the tumor microenvironment, boosting NK cell antitumor activity against Ab-coated tumor cells and ultimately increasing their production of interferon- γ (IFN γ ) [ 23 ].…”
Section: Mechanisms Of Action Of Her2-targeting Agentsmentioning
confidence: 79%
“…Most peripheral blood NK cells are CD56 + CD16 + effector cells, only a small part of which belongs to CD56 + CD16 − cells. Their function is regulated by a delicate balance between inhibitory and activating receptors, in which the CD16 low affinity receptor binds to the Fc end of IgG1 and mediates NK cells to recognize target cells through the Fab end of IgG1, so that the strong cytotoxic effects can be achieved [90]. This phenomenon is also called antibody-dependent cellular cytotoxicity (ADCC).…”
Section: Nkg2d Signaling Induces High Expression Of Cd16 On Nk Cells mentioning
confidence: 99%
“…It is reported that trastuzumab-induced ADCC could by augmented by enhancing NK cell activities [ 105 , 106 ], by modifying the antibody itself [ 107 , 108 , 109 ], and by inhibitors to various proteins including caspase [ 110 ], CD112R and TIGIT [ 111 ], Histone deacetylase (HDAC), and Adams [ 112 ]. Moreover, chemotherapeutic drug including Tanxanes [ 113 ] and tyrosine kinase inhibitors [ 114 , 115 ] are also found to enhance trastuzumab-mediated ADCC.…”
Section: Mechanisms Underlying the Action Of Trastuzumabmentioning
confidence: 99%