Using Magnetic Resonance Imaging to Evaluate Dendritic Cell-Based Vaccination

Peter M Ferguson,Angela Slocombe,Richard D Tilley,Ian F Hermans,T Mark Doherty

doi:10.1371/journal.pone.0065318

Abstract

Cancer immunotherapy with antigen-loaded dendritic cell-based vaccines can induce clinical responses in some patients, but further optimization is required to unlock the full potential of this strategy in the clinic. Optimization is dependent on being able to monitor the cellular events that take place once the dendritic cells have been injected in vivo, and to establish whether antigen-specific immune responses to the tumour have been induced. Here we describe the use of magnetic resonance imaging (MRI) as a simple, non-invasive approach to evaluate vaccine success. By loading the dendritic cells with highly magnetic iron nanoparticles it is possible to assess whether the injected cells drain to the lymph nodes. It is also possible to establish whether an antigen-specific response is initiated by assessing migration of successive rounds of antigen-loaded dendritic cells; in the face of a successfully primed cytotoxic response, the bulk of antigen-loaded cells are eradicated on-route to the node, whereas cells without antigen can reach the node unchecked. It is also possible to verify the induction of a vaccine-induced response by simply monitoring increases in draining lymph node size as a consequence of vaccine-induced lymphocyte trapping, which is an antigen-specific response that becomes more pronounced with repeated vaccination. Overall, these MRI techniques can provide useful early feedback on vaccination strategies, and could also be used in decision making to select responders from non-responders early in therapy.

Highlights

Dendritic cell (DC)-based vaccines can produce striking remissions of advanced disease [1,2], but the clinical response rate in most studies is less than 10% [3]
Using magnetic resonance imaging (MRI) to detect homing of DCs to lymph nodes To investigate the utility of using Fe NP in tracking DCs in vivo, we first assessed their uptake by murine bone marrow-derived DCs (BM-DCs), and compared this to uptake of IONP that had been prepared according to conventional methods [28], and coated with di-mercaptosuccinic acid (DMSA) in the same manner as was used for Fe NP [29]
This was confirmed by flame atomic absorption spectrometry, which showed that the amount of iron acquired by DCs from Fe NP and IONP was similar (10 pg Fe per cell) (Fig. 1B). When these DCs were dispersed in agar, and subject to MRI at 9.4 T, the cells incubated with Fe NP produced significantly greater change in T2 relaxation in vitro across a range of cell concentrations, with this ‘‘negative enhancement’’ apparent as dark regions on the scans (Fig. 1C, D). From this MRI data, the amount of T2 reduction per cell was calculated as 0.1% per cell for DCs incubated with Fe NP versus 0.05% per cell for those labelled with IO (95% C.I. 0.08–0.11 and 0.04–0.06 respectively)

Summary

Introduction

Dendritic cell (DC)-based vaccines can produce striking remissions of advanced disease [1,2], but the clinical response rate in most studies is less than 10% [3]. To improve the response rate to DC-based vaccination, there are numerous parameters yet to optimise, such as the process of ex-vivo generation, the antigen loading procedure, selecting the ideal subtype and activation state of the DCs, defining the best route of delivery, and defining the optimal dosing schedule. To investigate these factors, it is necessary to monitor the immune responses generated by vaccination. Following injection by the commonly used routes of delivery (subcutaneous, intradermal or intravenous), the DCs must migrate via the vascular or lymphatic networks to the local lymph nodes to present their antigens to T cells. Non-invasive imaging strategies that can be used to evaluate migration to the lymph nodes could be informative in this setting

Methods

Results

Conclusion