Abstract
The development of successful cancer vaccines is contingent on the ability to induce effective and persistent anti-tumor immunity against self-antigens that do not typically elicit immune responses. In this study, we examine the effects of a non-myeloablative dose of total body irradiation on the ability of tumor-naïve mice to respond to DNA vaccines against melanoma. We demonstrate that irradiation followed by lymphocyte infusion results in a dramatic increase in responsiveness to tumor vaccination, with augmentation of T cell responses to tumor antigens and tumor eradication. In irradiated mice, infused CD8+ T cells expand in an environment that is relatively depleted in regulatory T cells, and this correlates with improved CD8+ T cell functionality. We also observe an increase in the frequency of dendritic cells displaying an activated phenotype within lymphoid organs in the first 24 hours after irradiation. Intriguingly, both the relative decrease in regulatory T cells and increase in activated dendritic cells correspond with a brief window of augmented responsiveness to immunization. After this 24 hour window, the numbers of dendritic cells decline, as does the ability of mice to respond to immunizations. When immunizations are initiated within the period of augmented dendritic cell activation, mice develop anti-tumor responses that show increased durability as well as magnitude, and this approach leads to improved survival in experiments with mice bearing established tumors as well as in a spontaneous melanoma model. We conclude that irradiation can produce potent immune adjuvant effects independent of its ability to induce tumor ablation, and that the timing of immunization and lymphocyte infusion in the irradiated host are crucial for generating optimal anti-tumor immunity. Clinical strategies using these approaches must therefore optimize such parameters, as the correct timing of infusion and vaccination may mean the difference between an ineffective treatment and successful tumor eradication.
Highlights
Developing vaccines to prevent or treat malignancy represents an appealing strategy that could potentially be combined with conventional treatments
We found that irradiation prior to vaccination resulted in loss of responsiveness to immunizations, demonstrated by a reduction in T cell responses to peptide restimulation (Figure 1B) as well as an inferior ability to reject an intradermal challenge with murine B16 melanoma (Figure 1D)
We found that treating with radiation and lymphocyte infusion prior to vaccination led to increased T cell responses up to 19 days after the final immunization, though by day 35 these had waned to levels similar to unirradiated mice (Figure 4A)
Summary
Developing vaccines to prevent or treat malignancy represents an appealing strategy that could potentially be combined with conventional treatments. Clinical progress has recently been accelerating, with three Phase 3 clinical trials demonstrating a survival benefit with vaccine therapies directed against lymphoma, melanoma, and prostate cancer [3,4,5] These results affirm that cancer vaccines have an emerging role to play in the management of malignancy. Given the well-established ability of irradiation to augment adoptive T cell therapies, in this study we have hypothesized that irradiation would augment immune responses to a T cell cancer vaccine. Efficacy correlates with the presence of activated dendritic cells that presumably prime the observed larger population of vaccine-generated tumor antigen specific CD8+ T cells
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
