Trastuzumab mediates antibody-dependent cell-mediated cytotoxicity and phagocytosis to the same extent in both adjuvant and metastatic HER2/neu breast cancer patients

Petričević, Branka; Laengle, Johannes; Singer, Josef; Sachet, Monika; Fazekas, Judit; Steger, Guenther G.; Bartsch, Rupert; Jensen‐Jarolim, Erika; Bergmann, Michael

doi:10.1186/1479-5876-11-307

Cited by 152 publications

(94 citation statements)

References 61 publications

(59 reference statements)

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“…The modulation of signaling pathways was also shown to be a major mechanism when cell lines were treated with trastuzumab, whereas ADCC was the leading mechanism in small animals treated with the same molecule (28,29). The mechanism of action involved was also shown to vary depending on the neoadjuvant or adjuvant setting, dose and administration schedule and the presence or absence of co-administered drugs (28,30,31). In 2004, Gennari et al showed that trastuzumab employed the preferential immunological mechanism of ADCC when used as a monotherapy and in a preoperative setting (28).…”

Section: Discussionmentioning

confidence: 99%

Trastuzumab as a preoperative monotherapy does not inhibit HER2 downstream signaling in HER2-positive breast cancer

Lion¹,

Harlé²,

Salleron³

et al. 2016

Oncology Letters

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Abstract. Human epidermal growth factor 2 (HER2) is overexpressed in 15-20% of breast carcinomas. The overexpression of HER2 was previously associated with a poor prognosis until the development of the first anti-HER2 therapy, trastuzumab, which drastically improves the prognosis of HER2-overexpressing breast cancers. However, its mechanism of action remains not fully understood. Several studies have proposed that the behavior and mechanism of action of trastuzumab may be drastically altered in vitro and in vivo. The present study assesses the ability of trastuzumab to inhibit the phosphorylation of the key-proteins of phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin and Ras/Raf/mitogen-activated protein kinase (MAPK) signaling pathways in vitro, in breast cancer cell lines and in tumor biopsies obtained from patients treated with trastuzumab preoperative monotherapy as part of the Unicancer GEP04 RADHER phase II clinical trial. HER2-positive SKBR3 and HER2-negative MCF-7 cell lines were exposed to trastuzumab for 72 h. In total, 41 patients received trastuzumab alone for 6 weeks of preoperative treatment. Biopsies were collected at the baseline and at surgery. A total of 19 pairs of associated baseline and surgery tumor specimens were eligible for protein extraction and comparative phosphoprotein expression analysis, prior to and subsequent to treatment. The expression of phosphoproteins was quantitatively assessed using a multiplex immunoassay. In the SKBR3 cell line, a statistically significant decrease of the expression level of phosphorylated (p-)AKT, p-ribosomal protein S6 kinase B1, p-extracellular signal regulated kinase 1/2 and p-mitogen-activated protein kinase kinase 1 was observed after exposure to trastuzumab. In contrast, no statistically significant variations for levels expression of these phosphoproteins were observed in patients following treatment. The lack of downregulation of PI3K and MAPK pathways could probably be explained by the implementation of a predominant immunological mechanism of action for trastuzumab, a type of antibody-dependent cell-mediated toxicity, which has previously been reported in preoperative monotherapy settings. The present study confirms that trastuzumab involves various modes of action when assayed in vitro and used clinically.

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Section: Discussionmentioning

confidence: 99%

Trastuzumab as a preoperative monotherapy does not inhibit HER2 downstream signaling in HER2-positive breast cancer

Lion¹,

Harlé²,

Salleron³

et al. 2016

Oncology Letters

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“…Ab-dependent cellular phagocytosis (ADCP) mediated by activated macrophages can kill tumor cells (14). It has been reported that trastuzumab could mediate ADCP against HER2-expressing cancer cells by PBMCs (15) and macrophages (16) in vitro. However, the role of macrophages in response to trastuzumab in antitumor efficacy has not been established in vivo.…”

mentioning

confidence: 99%

Trastuzumab Triggers Phagocytic Killing of High HER2 Cancer Cells In Vitro and In Vivo by Interaction with Fcγ Receptors on Macrophages

Shi

Fan

Deng

et al. 2015

The Journal of Immunology

170

139

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Trastuzumab has been used for the treatment of HER2-overexpressing breast cancer for more than a decade, but the mechanisms of action for the therapy are still being actively investigated. Ab-dependent cell-mediated cytotoxicity mediated by NK cells is well recognized as one of the key mechanisms of action for trastuzumab, but trastuzumab-mediated Ab-dependent cellular phagocytosis (ADCP) has not been established. In this study, we demonstrate that macrophages, by way of phagocytic engulfment, can mediate ADCP and cancer cell killing in the presence of trastuzumab. Increased infiltration of macrophages in the tumor tissue was associated with enhanced efficacy of trastuzumab whereas depletion of macrophages resulted in reduced antitumor efficacy in mouse xenograft tumor models. Among the four mouse FcγRs, FcγRIV exhibits the strongest binding affinity to trastuzumab. Knockdown of FcγRIV in mouse macrophages reduced cancer cell killing and ADCP activity triggered by trastuzumab. Consistently, an upregulation of FcγRIV expression by IFN-γ triggered an increased ADCP activity by trastuzumab. In an analogous fashion, IFN-γ priming of human macrophages increased the expression of FcγRIII, the ortholog of murine FcγRIV, and increased trastuzumab-mediated cancer cell killing. Thus, in two independent systems, the results indicated that activation of macrophages in combination with trastuzumab can serve as a therapeutic strategy for treating high HER2 breast cancer by boosting ADCP killing of cancer cells.

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“…ADCP results from the binding of Abs to antigens on the surface of target cells and the binding of their Fc moieties to FcgRs on the surface of effector cells (11,18). There are more than five different isotypes of FcgRs, and the individual isotypes are expressed at various amounts on different effector cells involved in different effector functions (4 6).…”

Section: Discussionmentioning

confidence: 99%

“…Mogamulizumab, which is an anti-CC chemokine receptor 4 mAb that is defucosylated resulting in high affinity for FcgRIIIA, is anticipated to exert enhanced ADCC to kill tumour cells (9). Since the clinical effects of TRA involve ADCP as well as ADCC (10,11), modified TRA with enhanced effector functions is desired.…”

mentioning

confidence: 99%

Effect of trastuzumab interchain disulfide bond cleavage on Fcγ receptor binding and antibody-dependent tumour cell phagocytosis

et al. 2015

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The Fc domain of human IgG1 binds to Fcc receptors (FccRs) to induce effector functions such as phagocytosis. There are four interchain disulfide bonds between the H and L chains. In this study, the disulfide bonds within the IgG1 trastuzumab (TRA), which is specific for HER2, were cleaved by mild S-sulfonation or by mild reduction followed by S-alkylation with three different reagents. The cleavage did not change the binding activities of TRA to HER2-bearing SK-BR-3 cells. The binding activities of TRA to FccRIIA and FccRIIB were greatly enhanced by modification with mild reduction and S-alkylation with ICH 2 CONH 2 or N-(4-aminophenyl) maleimide, while the binding activities of TRA to FccRI and FccRIIIA were decreased by any of the four modifications. However, the interchain disulfide bond cleavage by the different modifications did not change the antibody-dependent cellmediated phagocytosis (ADCP) of SK-BR-3 cells by activated THP-1 cells. The order of FccR expression levels on the THP-1 cells was FccRII > FccRI > FccRIII and ADCP was inhibited by blocking antibodies against FccRI and FccRII. These results imply that the effect of the interchain disulfide bond cleavage on FccRs binding and ADCP is dependent on modifications of the cysteine residues and the FccR isotypes.

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Trastuzumab mediates antibody-dependent cell-mediated cytotoxicity and phagocytosis to the same extent in both adjuvant and metastatic HER2/neu breast cancer patients

Cited by 152 publications

References 61 publications

Trastuzumab as a preoperative monotherapy does not inhibit HER2 downstream signaling in HER2-positive breast cancer

Trastuzumab as a preoperative monotherapy does not inhibit HER2 downstream signaling in HER2-positive breast cancer

Trastuzumab Triggers Phagocytic Killing of High HER2 Cancer Cells In Vitro and In Vivo by Interaction with Fcγ Receptors on Macrophages

Effect of trastuzumab interchain disulfide bond cleavage on Fcγ receptor binding and antibody-dependent tumour cell phagocytosis

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