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Macrophages eliminate circulating tumor cells after monoclonal antibody therapy.

ABSTRACT: The use of monoclonal antibodies (mAbs) as therapeutic tools has increased dramatically in the last decade and is now one of the mainstream strategies to treat cancer. Nonetheless, it is still not completely understood how mAbs mediate tumor cell elimination or the effector cells that are involved. Using intravital microscopy, we found that antibody-dependent phagocytosis (ADPh) by macrophages is a prominent mechanism for removal of tumor cells from the circulation in a murine tumor cell opsonization model. Tumor cells were rapidly recognized and arrested by liver macrophages (Kupffer cells). In the absence of mAbs, Kupffer cells sampled tumor cells; however, this sampling was not sufficient for elimination. By contrast, antitumor mAb treatment resulted in rapid phagocytosis of tumor cells by Kupffer cells that was dependent on the high-affinity IgG-binding Fc receptor (Fc?RI) and the low-affinity IgG-binding Fc receptor (Fc?RIV). Uptake and intracellular degradation were independent of reactive oxygen or nitrogen species production. Importantly, ADPh prevented the development of liver metastases. Tumor cell capture and therapeutic efficacy were lost after Kupffer cell depletion. Our data indicate that macrophages play a prominent role in mAb-mediated eradication of tumor cells. These findings may help to optimize mAb therapeutic strategies for patients with cancer by helping us to aim to enhance macrophage recruitment and activity.

SUBMITTER: Gul N

PROVIDER: S-EPMC3904600 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Macrophages eliminate circulating tumor cells after monoclonal antibody therapy.

Gül Nuray N Babes Liane L Siegmund Kerstin K Korthouwer Rianne R Bögels Marijn M Braster Rens R Vidarsson Gestur G ten Hagen Timo L M TL Kubes Paul P van Egmond Marjolein M

The Journal of clinical investigation 20140116 2

The use of monoclonal antibodies (mAbs) as therapeutic tools has increased dramatically in the last decade and is now one of the mainstream strategies to treat cancer. Nonetheless, it is still not completely understood how mAbs mediate tumor cell elimination or the effector cells that are involved. Using intravital microscopy, we found that antibody-dependent phagocytosis (ADPh) by macrophages is a prominent mechanism for removal of tumor cells from the circulation in a murine tumor cell opsoniz ...[more]

PMID: 24430180

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Project description:BackgroundIn the era of personalized cancer medicine, identifying techniques for effectively matching patients to efficacious treatments is a critical step in the treatment process. The advent of anti-cancer immunotherapies necessitates novel approaches to biomarker identification beyond traditional genomic profiling. One promising approach is incorporation of nomograms into treatment decisions. Nomograms are prediction tools, based on statistical modeling, designed to predict treatment outcomes. As a first step toward developing a nomogram, we conducted analyses to predict CD137 expression of natural killer cells after monoclonal antibody (mAb) treatment.Patients and methodsPatient, tumor and immune characteristics were collected from 199 patients with breast cancer (N?=?62), head/neck cancers (N?=?46) and non-Hodgkin's lymphoma (NHL) (N?=?91), who were receiving mAb therapy as part of clinical trials. The difference in CD137 expression before and after mAb therapy was assessed by flow cytometry. To evaluate those who respond to mAb therapy via increased CD137 expression, we applied classification and regression trees (CART), multivariable lasso regression tools and Random Forest.ResultsThe CD137 expression was significantly different for each cancer type [mean (SD): Breast: 6.6 (6.5); Head/Neck: 11.0 (7.0); NHL: 7.5 (7.1), P?<?0.0001]. For breast cancer and NHL, FcR polymorphism and baseline CD137 expression were significant predictors of increased CD137 expression; for head/neck cancer, FcR polymorphism and age were significant predictors of increased expression.ConclusionsOur preliminary results suggest that FcR polymorphism, pre-treatment CD137 expression and age are significant predictors of CD137 upregulation in patients. This study demonstrates that the development of a nomogram for therapy response is feasible. Further work validating our models in an independent cohort will provide the next steps in developing a nomogram that may be used to individualize this therapeutic approach for patients (NCT01114256).

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Macrophages eliminate circulating tumor cells after monoclonal antibody therapy.

Publications

Macrophages eliminate circulating tumor cells after monoclonal antibody therapy.

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