Targeting T cell activation in immuno-oncology

Abstract

The years since 2009 have seen tremendous progress in unlocking the curative potential of the immune system for the treatment of cancer. Much of that revolution in immuno-oncology has been fueled by the clinical success of immune checkpoint inhibitors, particularly those targeting the PD-1 axis. Unfortunately, many patients still fail to benefit from checkpoint blockade or other immunotherapies. An inability to fully activate antitumour T cells contributes in part to the failure of those therapies. Here, we review the basic biology of T cell activation, with particular emphasis on the essential role of the dendritic cell and the innate immune system in T cell activation. The current understanding of the multiple factors that govern T cell activation and how they impinge on tumour immunotherapy are also discussed. Lastly, treatment strategies to potentially overcome barriers to T cell activation and to enhance the efficacy of immunotherapy are addressed.

Keywords: Immuno-oncology; T cell activation; immune checkpoint inhibitors.

FIGURE 1

The maturation status of dendritic cells (DCs) determines T cell activation or tolerance. Mature DCs provide T cells with signals through the T cell receptor (TCR) and through co-stimulatory receptors (co-stim) and cytokines, resulting in T cell activation. Immature DCs provide signals only through the TCR, which results in T cell tolerance. Maturation of DCs requires signals from the pattern recognition family of receptors.

FIGURE 2

Selection of co-stimulatory receptors and their ligands. Members of the immunoglobulin superfamily co-stimulatory receptors and their ligands depicted are CD28, inducible T cell co-stimulator (ICOS, CD278), and CD226. Members of the tumour necrosis factor receptor superfamily co-stimulatory receptors and their ligands depicted are CD27 (TNFRSF7), GITR (TNFRSF18), OX40 (CD134/TNFSF4), and 4-1BB (CD137/TNFRSF9). Abbreviations or other names for the ligands are B7-1 (CD80), B7-2 (CD86), ICOS ligand (ICOSL/B7-H2/CD275), OX40 ligand (OX40L/CD252), 4-1BB ligand (CD137L), GITR ligand (GITRL/TL6), and CD70 (TNFSF7). APC = antigen presenting cell.

FIGURE 3

Selection of co-inhibitory receptors and their ligands. Co-inhibitory molecular interactions include LAG-3 (CD223), TIM-3 (HAVCR2/CD366), TIGIT (VSTM3), CTLA-4 (CD152), and PD-1 (CD279). Abbreviations or other names for the ligands are FGL1, B7-1 (CD80), B7-2 (CD86), PD-L1 (B7-H1/CD274), and PD-L2 (B7-DC/CD273). Red boxes indicate molecules for which antibodies that block the interaction with the molecule’s target ligand are approved for clinical use. APC = antigen presenting cell.