Immune checkpoint inhibitors: recent progress and potential biomarkers

Pramod Darvin, Salman M Toor, Varun Sasidharan Nair, Eyad Elkord, Pramod Darvin, Salman M Toor, Varun Sasidharan Nair, Eyad Elkord

Abstract

Cancer growth and progression are associated with immune suppression. Cancer cells have the ability to activate different immune checkpoint pathways that harbor immunosuppressive functions. Monoclonal antibodies that target immune checkpoints provided an immense breakthrough in cancer therapeutics. Among the immune checkpoint inhibitors, PD-1/PD-L1 and CTLA-4 inhibitors showed promising therapeutic outcomes, and some have been approved for certain cancer treatments, while others are under clinical trials. Recent reports have shown that patients with various malignancies benefit from immune checkpoint inhibitor treatment. However, mainstream initiation of immune checkpoint therapy to treat cancers is obstructed by the low response rate and immune-related adverse events in some cancer patients. This has given rise to the need for developing sets of biomarkers that predict the response to immune checkpoint blockade and immune-related adverse events. In this review, we discuss different predictive biomarkers for anti-PD-1/PD-L1 and anti-CTLA-4 inhibitors, including immune cells, PD-L1 overexpression, neoantigens, and genetic and epigenetic signatures. Potential approaches for further developing highly reliable predictive biomarkers should facilitate patient selection for and decision-making related to immune checkpoint inhibitor-based therapies.

Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1. Overview of predictive biomarkers for…
Fig. 1. Overview of predictive biomarkers for response to ICIs.
The response to immune checkpoint inhibitors varies depending on the TME. In the responders, tumors have a high neoantigen load, high levels of TILs, especially effector cells, a high Teff to Treg ratio, low MDSC levels and increased secretion of IFN-γ and other cytokines (a). In nonresponders, the TME contains high levels of immunosuppressive cells, such as Tregs and MDSCs, and very low levels of NK cells and activated lymphocytes (b)
Fig. 2. Immune checkpoint blockade for T-cell…
Fig. 2. Immune checkpoint blockade for T-cell activation.
Immune checkpoints, including PD-1 and CTLA-4, expressed on activated T cells lead to inhibition of T-cell activation upon binding to their ligands on tumor cells/antigen-presenting cells. These interactions can be blocked using monoclonal antibodies, leading to the activation of T cells targeting tumor cells through the release of effector cytokines and cytotoxic granules.

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