Clinical Implications of Co-Inhibitory Molecule Expression in the Tumor Microenvironment for DC Vaccination: A Game of Stop and Go

Angela Vasaturo,Deborah G A Peeters,Jolanda M De Vries,Carl G Figdor,Stanleyson V Hato,Coco C H De Koning,Stefania Di Blasio

doi:10.3389/fimmu.2013.00417

Abstract

The aim of therapeutic dendritic cell (DC) vaccines in cancer immunotherapy is to activate cytotoxic T cells to recognize and attack the tumor. T cell activation requires the interaction of the T cell receptor with a cognate major-histocompatibility complex-peptide complex. Although initiated by antigen engagement, it is the complex balance between co-stimulatory and co-inhibitory signals on DCs that results in T cell activation or tolerance. Even when already activated, tumor-specific T cells can be neutralized by the expression of co-inhibitory molecules on tumor cells. These and other immunosuppressive cues in the tumor microenvironment are major factors currently hampering the application of DC vaccination. In this review, we discuss recent data regarding the essential and complex role of co-inhibitory molecules in regulating the immune response within the tumor microenvironment. In particular, possible therapeutic intervention strategies aimed at reversing or neutralizing suppressive networks within the tumor microenvironment will be emphasized. Importantly, blocking co-inhibitory molecule signaling, often referred to as immune checkpoint blockade, does not necessarily lead to an effective activation of tumor-specific T cells. Therefore, combination of checkpoint blockade with other immune potentiating therapeutic strategies, such as DC vaccination, might serve as a synergistic combination, capable of reversing effector T cells immunosuppression while at the same time increasing the efficacy of T cell-mediated immunotherapies. This will ultimately result in long-term anti-tumor immunity.

Highlights

The goal of cancer immunotherapy is to activate, or reactivate, the immune system in cancer patients for therapeutic benefit
Dendritic cells (DCs) must take up and present antigens derived from the tumor, which can be encountered in situ or delivered to the dendritic cells (DCs) ex vivo as part of a therapeutic vaccine
The introduction of ipilimumab to the clinic has provided a boost to cancer immunotherapy, keeping in mind that ipilimumab is the first anti-cancer treatment approved that does not target the tumor but rather targets the immune system

Summary

INTRODUCTION

The goal of cancer immunotherapy is to activate, or reactivate, the immune system in cancer patients for therapeutic benefit This is a challenging endeavor, as escape from immunosurveillance is an essential requirement for tumor progression. They do so by hiding from immune detection, blocking the function of immune cells, and/or by influencing immune cells to induce tolerance to the tumor and even to produce tumor growth enhancing factors Despite this escape from immunosurveillance, there is ample evidence indicating that it is possible to induce specific anti-tumor immune responses either naturally (spontaneous) or therapeutically. Dendritic cells (DCs) must take up and present antigens derived from the tumor, which can be encountered in situ or delivered to the DCs ex vivo as part of a therapeutic vaccine This has to be coupled to an activation or maturation signal to the DC.

Improving DC vaccination with checkpoint blockade

Findings

DISCUSSION AND FUTURE