Reversing T-cell exhaustion in immunotherapy: a review on current approaches and limitations

ABSTRACT

Introduction:T cell functions are altered during chronic viral infections and tumor development. This is mainly manifested by significant changes in T cells’ epigenetic and metabolic landscapes, pushing them into an ‘exhausted’ state. Reversing this T cell exhaustion has been emerging as a ‘game-changing’ therapeutic approach against cancer and chronic viral infection.

Areas covered:This review discusses the cellular pathways related to T cell exhaustion, and the clinical development and possible cellular targets that can be exploited therapeutically to reverse this exhaustion. We searched various databases (e.g. Google Scholar, PubMed, Elsevier, and other scientific database sites) using the keywords T cell exhaustion, T cell activation, co-inhibitory receptors, and reversing T cell exhaustion.

Expert opinion:The discovery of the immune checkpoints pathways represents a significant milestone toward understanding and reversing T cell exhaustion. Antibodies that target these pathways have already demonstrated promising activities in reversing T cell exhaustion. Nevertheless, there are still many associated limitations. In this context, next-generation alternatives are on the horizon. This includes the use of small molecules to block the immune checkpoints’ receptors, combining them with other treatments, and identifying novel, safer and more effective immunotherapeutic targets.

KEYWORDS:

• T-cell activation
• T-cell exhaustion
• immunotherapy
• reinvigoration
• inhibitory receptors

Article highlights

• T cell exhaustion is a state of T cells in which they lose their effector functions and proliferation capacity.

• Overexpression of co-inhibitory receptors (e.g. CTLA4 and PD1) is a hallmark of a progressing T cell exhaustion state and can be reversed by using immune checkpoints’ inhibitors.

• Cytokines play roles in activating T cells and an altered cytokine production is a character of T cell exhaustion.

• Activating co-stimulatory receptors can promote the reinvigoration of T cell exhaustion

• Further research is needed to better understand the signaling pathways that stimulate the reversal of T cell exhaustion.

• Preliminary clinical outcomes showed a great promise in combining immune checkpoints’ blockers with other types of treatment (e.g. chemotherapy, vaccination, radiation, stimulatory receptor agonists, or soluble mediators).

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This article is funded by the Alberta Cancer Foundation.