Abstract
The efficacy of cancer immunotherapy depends on the fine interplay between tumoral immune checkpoints and host immune system. However, the up-to-date clinical performance of checkpoint blockers in cancer therapy revealed that higher-level regulation should be further investigated for better therapeutic outcomes. It is becoming increasingly evident that the expression of immune checkpoints is largely associated to the immunotherapeutic response and consequent prognosis. Deubiquitinating enzymes (DUBs) with their role of cleaving ubiquitin from proteins and other molecules, thus reversing ubiquitination-mediated protein degradation, modulate multiple cellular processes, including, but not limited to, transcriptional regulation, cell cycle progression, tissue development, and antiviral response. Accumulating evidence indicates that DUBs also have the critical influence on anticancer immunity, simply by stabilizing pivotal checkpoints or key regulators of T-cell functions. Therefore, this review summarizes the current knowledge about DUBs, highlights the secondary checkpoint-like role of DUBs in cancer immunity, in particular their direct effects on the stability control of pivotal checkpoints and key regulators of T-cell functions, and suggests the therapeutic potential of DUBs-based strategy in targeted immunotherapy for cancer.
Highlights
As one kind of posttranslational modification, ubiquitination is mediated by a series of enzymatic reactions, mostly initiating protein degradation and affecting protein stability [1, 2]
The ubiquitin signal is modulated by an enzymatic cascade involving two ubiquitin-activating enzymes (E1), ∼40 ubiquitin-binding enzymes (E2), and more than 700 ubiquitin ligases (E3), as well as ∼100 of deubiquitinating enzymes (DUBs) [6,7,8]
In the first part of our review, we summarize the recent findings regarding the regulatory effects of three key DUBs, USP22, COP9 signalosome subunit 5 (CSN5), and USP9X, on PD-L1, the most representative immune checkpoint (Figure 2)
Summary
As one kind of posttranslational modification, ubiquitination is mediated by a series of enzymatic reactions, mostly initiating protein degradation and affecting protein stability [1, 2]. In addition to affecting tumor progression through the regulation of the cell cycle, USP22 can influence tumorigenesis and development by regulating immune cell infiltration through nuclear functions independent of its effects on PD-L1 protein stability [31].
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