Booster Vaccinations against Cancer Are Critical in Prophylactic but Detrimental in Therapeutic Settings

Alessia Ricupito,Arianna Calcinotto,Matteo Grioni,Anna Mondino,Renato Longhi,Matteo Bellone,Rodrigo Hess Michelini

doi:10.1158/0008-5472.can-12-2449

Abstract

Although cancer vaccines are in the clinic, several issues remain to be addressed to increase vaccine efficacy. In particular, whether how and how frequently a patient should be boosted remains to be defined. Here, we have assessed the ability of dendritic cell (DC)-based vaccines to induce a long-lasting tumor-specific CTL response in either prophylactic or therapeutic settings by taking advantage of transplantable and spontaneous mouse tumor models. Implementing a 24-hour ex vivo intracellular cytokine production assay, we have found that priming with a DC-based vaccine induced a long-lasting CTL response in wild-type mice, and homologous boosting better sustained the pool of central memory T cells, which associated with potent protection against B16F1 melanoma challenge. Appropriate timing of booster vaccination was also critical, as a tight boosting schedule hindered persistence of IFN-γ-competent memory CD8(+) T cells and mice survival in prophylactic settings. Conversely, prime/boost vaccination proved to be of no advantage or even detrimental in therapeutic settings in B16F1 and transgenic adenocarcinoma of the mouse prostate (TRAMP) models, respectively. Although DC priming was indeed needed for tumor shrinkage, restoration of immune competence, and prolonged survival of TRAMP mice, repeated boosting did not sustain the pool of central memory CTLs and was detrimental for mice overall survival. Thus, our results indicate that booster vaccinations impact antitumor immunity to different extents, depending on their prophylactic or therapeutic administration, and suggest evaluating the need for boosting in any given patient with cancer depending on the state of the disease.

Highlights

Vaccination strategies aimed at generating pools of memory CD8þ T cells have the potential to protect against diseases, such as intracellular pathogen infections (e.g., HIV and TBC) and tumors, which are otherwise resistant to humoral immunity generated by traditional vaccines [1].Dendritic cells (DC), either injected as vaccine or targeted in vivo by different antigenic formulations are the most potent vaccines to prime CTL responses [2]
Our results indicate that depending on the absence or the presence of active disease, prime-boost www.aacrjournals.org strategies result in very different cells fates, sustaining longterm memory in the former, whereas driving T-cell exhaustion in the latter
To enumerate long-lived memory T cells, DCs pulsed with Tag-IV (DC-Tag; refs. 14, 15), the immunodominant CTL epitope from the SV40 Tag Ag [23] were injected in WT mice

Summary

Introduction

Dendritic cells (DC), either injected as vaccine or targeted in vivo by different antigenic formulations are the most potent vaccines to prime CTL responses [2]. A homologous prime-boost strategy might not be optimal, as Ag-bearing DCs could be eliminated by effector and memory CTLs in previously vacci-. DCs are best at priming a tumorspecific response, but less effective than tumor cell lysates in boosting long-term immune memory [5]. Heterologous primeboost immunizations may favor a larger pool of Agspecific CTLs and select for high-affinity T cells [6]. Another unsolved matter is how frequently boosting should be conducted to optimize antitumor CTL responses. Multiple exogenous boosting might be deleterious, as repeated Ag encounter might lead lymphocytes to exhaustion and/or tolerance [8]

Methods

Results

Conclusion