Our current understanding of checkpoint inhibitor therapy in cancer immunotherapy

Abstract

Objective: Treatments with Food and Drug Administration-approved blocking antibodies targeting inhibitory cytotoxic T lymphocyte antigen 4 (CTLA4), programmed cell death protein 1 (PD-1) receptor, or programmed cell death ligand 1 (PD-L1), collectively named checkpoint inhibitors (CPIs), have been successful in producing long-lasting remissions, even in patients with advanced-stage cancers. However, these treatments are often accompanied by undesirable autoimmune and inflammatory side effects, sometimes bringing severe consequences for the patient. Rapid expansion of clinical applications necessitates a more nuanced understanding of CPI function in health and disease to develop new strategies for minimizing the negative side effects, while preserving the immunotherapeutic benefit.

Data sources: This review summarizes a new paradigm-shifting approach to cancer immunotherapy with the focus on the mechanism of action of immune checkpoints (CTLA4, PD-1, and its ligands).

Study selections: We performed a literature search and identified relevant recent clinical reports, experimental research, and review articles.

Results: This review highlights our understanding of the CPI mechanism of action on cellular and molecular levels. The authors also discuss how reactivation of T cell responses through the inhibition of CTLA4, PD-1, and PD-L1 is used for tumor inhibition in cancer immunotherapy.

Conclusion: Mechanisms of PD-1 and CTLA4 blockade and normal biological functions of these molecules are highly complex and require additional studies that will be critical for developing new approaches to dissociate the benefits of checkpoint blockade from off-target effects of the immune reactivation that leads to immune-related adverse events.

Figure 1.

Schematic representation of mechanisms of action of CTLA4 and PD-1-mediated inhibition of T cell activation. The progression of T-cell activation, their inhibition by normal regulatory mechanisms in the presence of CTLA4 (A) and PD-1 (B), and release of these negative regulations by anti-CTLA4, anti-PD-1, and anti-PD-L1 antibodies during cancer immunotherapy are outlined.

Figure 2.. Intracellular signaling by CTLA4 and PD-1

CTLA4 engagement by its ligands, CD80 and CD86, activates the serine/threonine phosphatase PP2A, which directly inhibits the TCR/CD28-mediated activation of AKT. PD-1 ligation by PD-L1 or PD-L2 leads to phosphorylation of tyrosine motifs in the PD-1 cytoplasmic domain, which results in recruitment of the tyrosine phosphatases SHP1 and SHP2, and inhibition of PI3K activity. PD-1 ligation also inhibits PLCγ1 and downstream Ras-MEK-ERK signaling. In contrast to PD-1, CTLA-4 has limited effects on Ras-MEK-ERK and PLCγ1 signaling inhibition.