Oncotarget

Research Papers:

IL-15 enhances the anti-tumor activity of trastuzumab against breast cancer cells but causes fatal side effects in humanized tumor mice (HTM)

Anja K. Wege _, Florian Weber, Alexander Kroemer, Olaf Ortmann, Falk Nimmerjahn and Gero Brockhoff

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Oncotarget. 2017; 8:2731-2744. https://doi.org/10.18632/oncotarget.13159

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Abstract

Anja K. Wege1, Florian Weber2, Alexander Kroemer3, Olaf Ortmann1, Falk Nimmerjahn4, Gero Brockhoff1

1Department of Gynecology and Obstetrics, University Medical Center Regensburg, 93053 Regensburg, Germany

2Institute of Pathology, University Hospital Regensburg, 93053 Regensburg, Germany

3MedStar Georgetown Transplant Institute, Georgetown University Hospital, Washington, DC, USA

4Institute of Genetics, Department of Biology, University of Erlangen-Nuremberg, 91058, Erlangen, Germany

Correspondence to:

Anja K. Wege, email: anja.wege@ukr.de

Keywords: humanized tumor mice (HTM), trastuzumab, IL-15, immunomodulation, breast cancer

Received: August 17, 2016    Accepted: October 13, 2016    Published: November 07, 2016

ABSTRACT

Cancer immunotherapy has been shown to enhance established treatment regimens. We evaluated the potential reinforcing effect of IL-15 in trastuzumab treated humanized tumor mice (HTM) which were generated by concurrent transplantation of neonatal NOD-scid IL2Rγnull mice with human hematopoietic stem cells (HSC) and HER2 positive breast cancer cells (metastasizing SK-BR-3, solid tumor forming BT474).

We found that trastuzumab treatment efficacy mainly depends on the immediate anti-tumorigenic cellular effect which is significantly enhanced by tumor interacting immune cells upon cotransplantion of HSC. However, trastuzumab treatment caused elevated CD44 expression on tumor cells that metastasized into the lung and liver but did not hinder tumor cell dissemination into the bone marrow. Moreover, in a number of SK-BR-3-transplanted animals disseminated CD44high/CD24low tumor cells lost trastuzumab sensitivity. Concerning the FcγRIIIa polymorphism, trastuzumab treatment efficiency in HTM was higher in mice with NK-cells harboring the high affinity FcγRIIIa compared to those with low affinity FcγRIIIa. In contrast, IL-15 caused the strongest NK-cell activation in heterozygous low affinity FcγRIIIa animals. Although IL-15 enhanced the trastuzumab mediated tumor defense, an unspecific immune stimulation resulted in preterm animal death due to systemic inflammation. Overall, treatment studies based on “patient-like” HTM revealed critical and adverse immune-related mechanisms which must be managed prior to clinical testing.


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