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-bethigh, PD-1int), 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.

First‐line pembrolizumab for non–small cell lung cancer patients with PD‐L1 ≥50% in a multicenter real‐life cohort: The PEMBREIZH study

“…New immunotherapies, known as immune checkpoint inhibitors, have also played an integral role in advancing outcomes for patients with advanced NSCLC in recent years. These drugs are monoclonal antibodies that bind to and interfere with negative regulator receptors on T lymphocytes, which in turn allow the lymphocytes to remain active and target NSCLC cells . The programmed death‐1 (PD‐1) inhibitors, such as nivolumab and pembrolizumab, are humanized monoclonal antibodies that block the PD‐1 receptor, a negative regulator on lymphocytes.…”

Reinforce the antitumor activity of CD8+ T cells via glutamine restriction

“…Therefore, a better understanding of CD8 + T activation is required for the development of successful tumor therapies. It is well‐known that inhibitory receptors such as programmed death 1 (PD‐1) and cytotoxic T‐lymphocyte‐associated protein 4 (CTLA‐4) can inhibit the function of tumor‐specific T cells by interacting with their ligands in the tumor microenvironment . Accordingly, PD‐1‐and CTLA‐4‐targeted therapies are effective for the treatment of tumors through the restoration of the immune response of exhausted T cells .…”

Follicular Lymphoma: Recent and Emerging Therapies, Treatment Strategies, and Remaining Unmet Needs

“…The programmed cell death‐1 (PD‐1) protein is widely expressed and found on activated T cells, B cells, and natural killer (NK) cells . PD‐1 binding to programmed death ligand‐1 and ligand‐2 produces inhibitory signals leading to T‐cell apoptosis.…”