Abstract
The advent of T-cell-based immunotherapy has remarkably transformed cancer patient treatment. Despite their success, the currently approved immunotherapeutic protocols still encounter limitations, cause toxicity, and give disparate patient outcomes. Thus, a deeper understanding of the molecular mechanisms of T-cell activation and inhibition is much needed to rationally expand targets and possibilities to improve immunotherapies. Protein ubiquitination downstream of immune signaling pathways is essential to fine-tune virtually all immune responses, in particular, the positive and negative regulation of T-cell activation. Numerous studies have demonstrated that deregulation of ubiquitin-dependent pathways can significantly alter T-cell activation and enhance antitumor responses. Consequently, researchers in academia and industry are actively developing technologies to selectively exploit ubiquitin-related enzymes for cancer therapeutics. In this review, we discuss the molecular and functional roles of ubiquitination in key T-cell activation and checkpoint inhibitory pathways to highlight the vast possibilities that targeting ubiquitination offers for advancing T-cell-based immunotherapies.
Highlights
For T cells to become activated upon encountering an antigen, a series of quantitative and qualitative signals have to be received by receptors at the cell surface and successfully integrate with numerous intracellular signaling cascades that eventually dictate an appropriate immune response [1]
Other important co-receptors are OX40, 4-1BB, ICOS, GITR, and CD27, which are usually expressed upon T-cell activation to regulate different aspects of T cells, including proliferation, the effector functions, generation of T-cell memory, induction of specific T-cell lineages, and importantly, similar to CD28, can impact anti-tumor responses [80]. 4-1BB and OX40 are co-stimulatory receptors belonging to tumor necrosis factor receptor (TNFR) family and are expressed on activated T cells
Current T-cell targeted cancer immunotherapy protocols leverage the most proximal events at the cell surface of T cells to enhance and reconstitute tumoral immune responses. This is accomplished either by blocking the receptor-ligand interaction of key inhibitory surface co-receptors, such as CTLA-4 and PD-1, a therapy known as checkpoint inhibition [111], or potentiating T-cell activation by using gene-edited and improved T-cell receptors, especially chimeric antigen receptor (CAR) T-cell therapy [112]
Summary
For T cells to become activated upon encountering an antigen, a series of quantitative and qualitative signals have to be received by receptors at the cell surface and successfully integrate with numerous intracellular signaling cascades that eventually dictate an appropriate immune response [1]. Immunotherapies that activate the patient’s own immune system, cytotoxic T cells, for stronger, specific, and lasting anti-tumor immune responses have modernized cancer therapy, complementing the more traditional protocols primarily targeting the tumorigenic cells. Their clinical outcomes are in general very encouraging, they have failed to provide universal care and can have toxicities associated, such as cytokine release syndrome, inflammation of diverse organs, including the nervous system, the liver, the skin and the intestines, as well as diverse cytopenias, specially neutropenia [8,9,10,11]. We will focus on revising the molecular and functional roles of ubiquitinating and deubiquitinating enzymes in key pathways of T-cell activation and inhibition that can offer alternatives for enhancing T-cell anti-tumor responses in cancer immunotherapy
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