Mechanisms of action and rationale for the use of checkpoint inhibitors in cancer

Clemence Granier; Eleonore De Guillebon; Charlotte Blanc; Helene Roussel; Cecile Badoual; Elia Colin; Antonin Saldmann; Alain Gey; Stephane Oudard; Eric Tartour

doi:10.1136/esmoopen-2017-000213

Mechanisms of action and rationale for the use of checkpoint inhibitors in cancer

ESMO Open. 2017 Jul 3;2(2):e000213. doi: 10.1136/esmoopen-2017-000213. eCollection 2017.

Authors

Clemence Granier^{1

2}, Eleonore De Guillebon^{1

2

3}, Charlotte Blanc^{1

2}, Helene Roussel^{1

2

4}, Cecile Badoual^{1

2

4}, Elia Colin^{1

2}, Antonin Saldmann^{1

2

5}, Alain Gey^{1

2

5}, Stephane Oudard^{1

2

3}, Eric Tartour^{1

5}

Affiliations

¹ INSERM U970, Université Paris Descartes Sorbonne Paris-Cité, Paris, France.
² Equipe Labellisée Ligue Contre le Cancer, Paris, France.
³ Department of medical oncology, Hopital Européen Georges Pompidou, Paris, France.
⁴ Department of Pathology, Hôpital Européen Georges Pompidou, Paris, France.
⁵ Department of Immunology, Hôpital Européen Georges Pompidou, Paris, France.

Abstract

The large family of costimulatory molecules plays a crucial role in regulation of the immune response. These molecules modulate TCR signalling via phosphorylation cascades. Some of the coinhibitory members of this family, such as PD-1 and CTLA-4, already constitute approved targets in cancer therapy and, since 2011, have opened a new area of antitumour immunotherapy. Many antibodies targeting other inhibitory receptors (Tim-3, VISTA, Lag-3 and so on) or activating costimulatory molecules (OX40, GITR and so on) are under evaluation. These antibodies have multiple mechanisms of action. At the cellular level, these antibodies restore the activation signalling pathway and reprogram T cell metabolism. Tumour cells become resistant to apoptosis when an intracellular PD-L1 signalling is blocked. CD8⁺ T cells are considered to be the main effectors of the blockade of inhibitory receptors. Certain CD8⁺ T cell subsets, such as non-hyperexhausted (CD28⁺, T-bet^high, PD-1^int), follicular-like (CXCR-5⁺) or resident memory CD8⁺ T cells, are more prone to be reactivated by anti-PD-1/PD-L1 monoclonal antibody (mAb). In the future, the challenge will be to rationally combine drugs able to make the tumour microenvironment more permissive to immunotherapy in order to potentiate its clinical activity.

Keywords: CD8+T cells; checkpoint inhibitors; exhaustion; immunotherapy; tumor microenvironment.

Publication types

Review