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Targeting the Ubiquitination/Deubiquitination Process to Regulate Immune Checkpoint Pathways

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Targeting the Ubiquitination/Deubiquitination Process to Regulate Immune Checkpoint Pathways Signal Transduction and Targeted Therapy www.nature.com/sigtrans REVIEW ARTICLE OPEN Targeting the ubiquitination/deubiquitination process to regulate immune checkpoint pathways Jiaxin Liu 1,2, Yicheng Cheng3, Ming Zheng4, Bingxiao Yuan4, Zimu Wang1,2, Xinying Li1,2, Jie Yin2, Mingxiang Ye2 and Yong Song2 The immune system initiates robust immune responses to defend against invading pathogens or tumor cells and protect the body from damage, thus acting as a fortress of the body. However, excessive responses cause detrimental effects, such as inflammation and autoimmune diseases. To balance the immune responses and maintain immune homeostasis, there are immune checkpoints to terminate overwhelmed immune responses. Pathogens and tumor cells can also exploit immune checkpoint pathways to suppress immune responses, thus escaping immune surveillance. As a consequence, therapeutic antibodies that target immune checkpoints have made great breakthroughs, in particular for cancer treatment. While the overall efficacy of immune checkpoint blockade (ICB) is unsatisfactory since only a small group of patients benefited from ICB treatment. Hence, there is a strong need to search for other targets that improve the efficacy of ICB. Ubiquitination is a highly conserved process which participates in numerous biological activities, including innate and adaptive immunity. A growing body of evidence emphasizes the importance of ubiquitination and its reverse process, deubiquitination, on the regulation of immune responses, providing the rational of simultaneous targeting of immune checkpoints and ubiquitination/deubiquitination pathways to enhance the therapeutic efficacy. Our review will summarize the latest findings of ubiquitination/deubiquitination pathways for anti-tumor immunity, and discuss therapeutic significance of targeting ubiquitination/deubiquitination pathways in the future of immunotherapy. 1234567890();,: Signal Transduction and Targeted Therapy (2021) ;6:28 https://doi.org/10.1038/s41392-020-00418-x INTRODUCTION combined with ICB treatments to improve their efficacy and The immune system, including the innate and adaptive immune overcome the challenges in the era of immunotherapy. systems, helps to defend against pathogens and tumors and Ubiquitination is a highly conserved posttranslational modifica- prevent damage to tissues, thus maintaining organismal home- tion in mammals. Ubiquitination is a stepwise process that is ostasis. Given that overactive immune responses can be detri- carried out by ubiquitin-activating enzyme E1, ubiquitin- mental (inflammatory or autoimmune diseases), immune conjugating enzyme E2, and ubiquitin ligase E3. Ubiquitination checkpoints, which are a set of molecules including cytotoxic involves the transfer of the C-terminal glycine of ubiquitin to an T lymphocyte-associated protein-4 (CTLA-4), programmed cell- ε-NH2 group of a lysine residue in a substrate.8,9 Ubiquitination death protein-1(PD-1), lymphocyte activation gene-3 (LAG-3), T cell can be classified into three major categories, including mono- immunoglobulin and ITIM domain (TIGIT), and T cell immunoglo- ubiquitination, multiubiquitination, and polyubiquitination, which bulin and mucin domain-containing-3 (TIM-3), are needed to results in proteolysis and signal transduction. In contrast, suppress excessive immune responses, maintain self-tolerance and ubiquitination can be reversed by deubiquitinases (DUBs) via avoid self-damage.1 However, tumors can also utilize the immune the removal of ubiquitin chains, leading to the termination of checkpoint pathways to inhibit anti-tumor immune response and ubiquitination and the preservation of substrate protein expres- evade immune surveillance, eventually resulting in tumor out- sion.10,11 The interaction between ubiquitination and deubiquiti- growth and progression.2 Hence, drugs that target immune nation plays crucial roles in almost all aspects of biological checkpoints have been developed over recent decades. In activities.12 Strikingly, multiple processes involved in innate and particular, the use of immune checkpoint blockade (ICB) has adaptive immunity, such as antigen presentation, cell differentia- achieved great success in cancer therapy since the first ICB tion, immune defense, and inflammatory responses, are regulated treatment, ipilimumab (anti-CTLA-4), was approved by the U.S. Food by ubiquitination/ deubiquitination.13–15 and Drug Administration (FDA) in 2011 for the treatment of Taken together, the ubiquitination/deubiquitination pathways metastatic melanoma.3 Nevertheless, ICB treatment is still limited may become potential therapeutic targets for the treatment of due to low response rates, de novo or acquired resistance and cancers, infections, and autoimmune diseases. Our review will inevitable immunotherapy-related adverse events (irAEs).4–7 There- summarize the research progress and the latest findings about fore, there is an urgent need to identify new strategies that can be the interactions between immune checkpoint pathways and 1Department of Respiratory and Critical Care Medicine, Affiliated Jinling Hospital, Medical School of Nanjing University, 210002 Nanjing, Jiangsu, China; 2Department of Respiratory and Critical Care Medicine, Jinling Hospital, Nanjing University School of Medicine, 210002 Nanjing, China; 3Department of Stomatology, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, China and 4Department of Respiratory and Critical Care Medicine, Jinling Hospital, Nanjing Medical University, 210002 Nanjing, Jiangsu, China Correspondence: Jie Yin ([email protected]) or Mingxiang Ye ([email protected]) or Yong Song ([email protected]) These authors contributed equally: Jiaxin Liu, Yicheng Cheng Received: 3 August 2020 Revised: 13 October 2020 Accepted: 27 October 2020 © The Author(s) 2021 Targeting the ubiquitination/deubiquitination process to regulate immune. Liu et al. 2 Table 1. A summary of immune checkpoint molecules Molecules Full name Alternate name Binding partners Expressed cells References CTLA-4 Cytotoxic T lymphocyte- CD152 CD80 (B7-1) T cells 5,139 associated protein-4 CD86 (B7-2) PD-1 Programmed cell-death CD279 PD-L1 (B7-H1 or CD274) T cells, NKT cells, B cells, 16,140 protein-1 PD-L2 (B7-DC or CD273) monocytes, Langerhans’ cells LAG-3 Lymphocyte activation gene-3 CD223 MHC-II T cells, B cells, 5,141,142 FGL1 Tregs, galectin-3 (LGALS3) NK cells, LSECtin NKT cells, α-synuclein pDCs TIGIT T-cell immunoglobulin WUCAM Vstm3 CD155 (PVR, Necl-5) T cells, Tregs, NK cells, 143–145 and ITIM domain Vsig9 CD112 (nectin-2, PRR2, PVRL2) TIM-3 T-cell immunoglobulin HAVCR2 Galectin-9 T cells, Tregs, DCs, 5,18,144–146 and mucin-domain containing-3 CD366 Ceacam-1 NK cells, monocytes, HMGB-1 macrophages PtdSer BTLA B and T cell CD272 HVEM B cells, T cells, 147,148 lymphocyte attenuator macrophages, DCs VISTA V-domain Ig PD-1H VSIG-3 APCs, T cells, Tregs 5,149 suppressor of DD1α T cell activation Gi24 Dies1 B7-H5 B7-H3 B7 homolog 3 protein CD276 IL20RA T cells, B cells, APCs, NK cells, 5,145,150–153 TLT2 (putative) DCs, monocytes, fibroblasts, epithelial cells, tumor cells B7-H4 B7 homolog 4 protein VTC1 B7x B7S1 unknown T cells, B cells, 145,154,155 monocytes, DCs KIR Killer-cell immunoglobulin-like CD158 MHC class I molecules NK cells, T cells 111,156 receptor CD160 Cluster of differentiation 160 – HVEM NK cells, T cells, 157 intraepithelial lymphocytes CD73 Cluster of differentiation 73 ecto-5’- Dephosphorylating extracellular AMP to Tumor cells, Th cells, Tregs, 158,159 nucleotidase generate adenosine T cells, B cells, macrophages, DCs CD96 Cluster of differentiation 96 – CD111 T cells, NK cells, NKT cells 160,161 CD155 ubiquitination/deubiquitination in cancers, infections, and auto- have been made to develop immune checkpoint inhibitors (ICIs) immune diseases, and discuss targeting ubiquitination/deubiqui- and test their safety and efficacy in various human malignancies. tination as a potential strategy for immunotherapy. Given the great success of anti-CTLA4 and anti-PD-1/PD-L1 therapies in a panel of multicenter randomized clinical trials, several ICIs have been approved by the FDA as front-line IMMUNE CHECKPOINTS treatments for melanoma,21–23 non-small cell lung cancer The full activation of T cells requires the simultaneous coactivation (NSCLC)24,25 and other cancers.4 of three signalings: (1) the T cell receptor (TCR) binds to a major Unfortunately, only a small group of cancer patients can benefit histocompatibility complex (MHC)–peptide complex presented by from ICIs, and the overall response rate to ICI single-agent therapy antigen-presenting cells (APCs); (2) CD80/CD86 expressed by APCs is less than 30%. In addition, there are emerging challenges binds to the costimulatory molecule CD28 expressed by T cells; regarding resistance to ICIs and irAEs in clinical settings.4 and (3) cytokines either enhance or suppress immune Identification of biomarkers that predict the response to ICI responses.16–18 However, overactivation of the immune response therapy would help clinicians to select patients who would benefit leads to a series of human illnesses, including autoimmune from ICI therapy and elucidate the mechanisms of resistance. We diseases.10 Therefore, there are negative feedback mechanisms and others have demonstrated that protein ubiquitination/ which function as brakes to limit the activity of T cells and deubiquitination not only results in proteolysis, but also mediates suppress immune cell-mediated tissue damage.19 These brakes cell
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