Cancer immunotherapy: co-stimulatory agonists and co-inhibitory antagonists

Abstract

The generation and maintenance of immune responses are controlled by both co-stimulatory and co-inhibitory signalling through T cell co-receptors, many of which belong to the immunoglobulin-like superfamily or the tumour necrosis factor receptor superfamily. Agonistic or antagonistic monoclonal antibodies targeting these co-receptors have the potential to enhance immunity. Furthermore, their activity on the immunosuppressive regulatory T cell populations which are prevalent within many tumours provides an additional rationale for their use as anti-cancer therapies. This review summarizes the interactions between cancer and the immune system, highlighting the ways in which these new classes of immunostimulatory antibodies might enhance anti-tumour immunity and summarizing early clinical experience with their use.

Fig. 1

Potential immunomodulatory targets for monoclonal antibody therapy. In the case of effector T cells, agonistic antibodies directed towards co-stimulatory pathways and antagonistic or blocking antibodies directed towards co-inhibitory pathways can directly enhance effector numbers, functions or persistence. The situation with respect to regulatory T cell populations remains less clear, but it appears likely from the current literature that agonists of classic co-stimulatory molecules may abrogate function, whereas blockade of cytotoxic T lymphocyte-associated-antigen 4 may also reduce suppressor function.