Low Dose Focused Ultrasound Induces Enhanced Tumor Accumulation of Natural Killer Cells

Naomi S Sta Maria,Michael R Weist,Samuel R Barnes,Andrew A Raubitschek,Russell E Jacobs,David Colcher,Mario U Mondelli

doi:10.1371/journal.pone.0142767

Naomi S Sta Maria, Michael R Weist + Show 5 more

Open Access

https://doi.org/10.1371/journal.pone.0142767

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Journal: PloS one	Publication Date: Nov 10, 2015
Citations: 24	License type: CC BY 4.0

Affiliation: California Institute of Technology, City of Hope

Abstract

Natural killer (NK) cells play a vital antitumor role as part of the innate immune system. Efficacy of adoptive transfer of NK cells depends on their ability to recognize and target tumors. We investigated whether low dose focused ultrasound with microbubbles (ldbFUS) could facilitate the targeting and accumulation of NK cells in a mouse xenograft of human colorectal adenocarcinoma (carcinoembryonic antigen (CEA)-expressing LS-174T implanted in NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) mice) in the presence of an anti-CEA immunocytokine (ICK), hT84.66/M5A-IL-2 (M5A-IL-2). Human NK cells were labeled with an FDA-approved ultra-small superparamagnetic iron oxide particle, ferumoxytol. Simultaneous with the intravenous injection of microbubbles, focused ultrasound was applied to the tumor. In vivo longitudinal magnetic resonance imaging (MRI) identified enhanced accumulation of NK cells in the ensonified tumor, which was validated by endpoint histology. Significant accumulation of NK cells was observed up to 24 hrs at the tumor site when ensonified with 0.50 MPa peak acoustic pressure ldbFUS, whereas tumors treated with at 0.25 MPa showed no detectable NK cell accumulation. These clinically translatable results show that ldbFUS of the tumor mass can potentiate tumor homing of NK cells that can be evaluated non-invasively using MRI.

Highlights

Natural killers (NK) cells are critical components of the immune system that show promise in cancer immunotherapy based on their ability to lyse malignant and infected cells without prior sensitization or immunization [1, 2]
Our study shows that administration of Low Dose Bubble-mediated Focused Ultrasound (ldbFUS) onto the tumor mass facilitates accumulation of adoptively transferred NK cells in a human cancer xenograft
LS-174T tumors treated with ldbFUS at 0.50MPa had substantial accumulation of NK cells compared to non ldbFUS treated tumors, as measured by in vivo magnetic resonance imaging (MRI) ΔR2Ã increases following administration of ferumoxytollabeled NK cells

Summary

Introduction

Natural killers (NK) cells are critical components of the immune system that show promise in cancer immunotherapy based on their ability to lyse malignant and infected cells without prior sensitization or immunization [1, 2]. NK cells have the ability to discriminate between “normal self” and “altered-self” through MHC class I—specific inhibitory receptors and activating receptors (“missing-self recognition”) [1]. It is the balance between inhibitory and activating receptors that direct NK cell activity. Activating receptors recognize upregulated proteins or pathogen-encoded ligands expressed by infected or tumor transformed cells and not by the host cells [1, 3].

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