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

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.

Figure 1

Mechanisms mediating the clinical activities of anti-PD-1/PD-L1/CTLA-4 antibodies. Various complementary mechanisms may account for the clinical activity of blockade of the PD-1–PD-L1 axis or CTLA-4 inhibitory receptors. Only antibodies with isotypes activating Fc receptors on macrophages or NK cells, such as ipilimumab, are able to mediate ADCC (ie, IgG1 isotype). Anti-PD-1 and anti-CTLA-4 antibodies reverse inhibitory signals transmitted to T cells and allow metabolic reprogramming of T cells. Reverse signalling of PD-L1 on tumour cells may also be affected by blocking the PD-L1–PD-1 interaction. ADCC, antibody-dependent cellular cytotoxicity.

Figure 2

Immune cells targeted by anti-PD-1/PD-L1 and anti-CTLA-4. anti-CTLA-4 monoclonal antibody with an IgG1 isotype depletes intratumoural regulatory T cells. In chronic infection and cancer, various PD-1⁺CD8⁺ T cells have been shown to proliferate or to be activated in response to anti-PD-1/PD-L1 therapy. The overlapping phenotype between these various subpopulations of CD8⁺ T cells is under investigation.