Abstract

BackgroundAdoptive T cell-transfer (ATC) therapy is a highly promising cancer-treatment approach. However, in vivo-administered T cells tend to disperse, with only a small proportion reaching the tumour. To remedy this, magnetic targeting of T cells has been recently explored. Magnetic nanoparticles (MNPs) functionalised with antibodies were attached to effector T cells and magnetically recruited to tumour sites under MRI guidance. In this study, we investigated whether 3-aminopropyl-triethoxysilane (APS)-coated MNPs directly attached to CD8+ T cell membranes could also magnetically target and accumulate tumour-specific CD8+ T cells in solid tumours using an external magnetic field (EMF). As it has been shown that T cells associated with APS-coated MNPs are retained in lymph nodes (LNs), and tumour-draining LNs are the most common sites of solid-tumour metastases, we further evaluated whether magnetic targeting of APS-MNP-loaded CD8+ T cells could cause them to accumulate in tumour-draining LNs.ResultsFirst, we show that antigen-specific CD8+ T cells preserve their antitumor activity in vitro when associated with APS-MNPs. Next, we demonstrate that the application of a magnetic field enhanced the retention of APS-MNP-loaded OT-I CD8+ T cells under flow conditions in vitro. Using a syngeneic mouse model, we found similar numbers of APS-MNP-loaded OT-I CD8+ T cells and OT-I CD8+ T cells infiltrating the tumour 14 days after cell transfer. However, when a magnet was placed near the tumour during the transfer of tumour-specific APS-MNP-loaded CD8+ T cells to improve tumour infiltration, a reduced percentage of tumour-specific T cells was found infiltrating the tumour 14 days after cell transfer, which was reflected in a smaller reduction in tumour size compared to tumour-specific CD8+ T cells transferred with or without MNPs in the absence of a magnetic field. Nonetheless, magnet placement near the tumour site during cell transfer induced infiltration of activated tumour-specific CD8+ T cells in tumour-draining LNs, which remained 14 days after cell transfer.ConclusionsThe use of an EMF to improve targeting of tumour-specific T cells modified with APS-MNPs reduced the percentage of these cells infiltrating the tumour, but promoted the retention and the persistence of these cells in the tumour-draining LNs.

Highlights

  • Adoptive T cell-transfer (ATC) therapy is a highly promising cancer-treatment approach

  • The hydrodynamic size and the Z-potential of these Magnetic nanoparticles (MNPs) were analysed by dynamic light scattering (DLS), the presence of coatings was verified by infrared spectrophotometry, and organic composition was examined by thermogravimetric analysis

  • In this work we explore whether the combined use of APS-MNPs, which can be directly attached to the cell membrane of T cells, and the application of external magnetic field (EMF) near a tumour in a mouse model of cancer in which the tumour expresses an antigen recognised by the transferred T cells could promote the accumulation of tumour-specific ­CD8+ T cells in the tumour region in adoptive cell therapy (ACT) therapies

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Summary

Introduction

Adoptive T cell-transfer (ATC) therapy is a highly promising cancer-treatment approach. ACT effectiveness depends on a number of factors, including the proliferation potential of transferred cells [10, 11], their persistence [12] or differentiation state [13], and their ability to migrate to and infiltrate the tumour [14, 15]. Another potential hurdle when applying ATC concerns the need to isolate and expand a large enough number of tumour-specific T cells for transfer [16]

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