Ya-Tao Wang
Wei-Dong Ji1†
Qi-Bing Liu- 1First People’s Hospital of Shangqiu, Henan Province, Shangqiu, China
- 2Department of Pharmacy, the First Affiliated Hospital of Hainan Medical University, Haikou, China
- 3Department of Pharmacology, School of Basic Medicine and Life Sciences, Hainan Medical University, Haikou, China
Immune dysfunction has been proposed as a factor that may contribute to disease progression. Emerging evidence suggests that immunotherapy aims to abolish cancer progression by modulating the balance of the tumor microenvironment. 4-1BB (also known as CD137 and TNFRS9), a member of tumor necrosis factor receptor superfamily, has been validated as an extremely attractive and promising target for immunotherapy due to the upregulated expression in the tumor environment and its involvement in tumor progression. More importantly, 4-1BB-based immunotherapy approaches have manifested powerful antitumor effects in clinical trials targeting 4-1BB alone or in combination with other immune checkpoints. In this review, we will summarize the structure and expression of 4-1BB and its ligand, discuss the role of 4-1BB in the microenvironment and tumor progression, and update the development of drugs targeting 4-1BB. The purpose of the review is to furnish a comprehensive overview of the potential of 4-1BB as an immunotherapeutic target and to discuss recent advances and prospects for 4-1BB in cancer therapy.
Introduction
Tumor immunotherapy exerts antitumor efficacy through the interaction of the host immune system with tumor-associated antigens (1). It can restore or enhance the body’s immune system’s natural defenses against tumors, which typically targets specific biomolecules on the surface of cancer cells, exemplified by tumor-associated antigens (2). Immunotherapy including immune checkpoint inhibitor (ICI) and CAR-T therapy has made breakthroughs in tumor treatment, but the overall response rate is not high, and many patients cannot benefit from it (3–6). Therefore, the development of new immune checkpoints and biomarkers and expansion of the beneficiary population from immunotherapy are urgent problems to be solved.
Neoantigen epitopes generated by somatic mutations in cancer cells play an important role in T-cell immune responses, which have become an important driver of immune checkpoint discovery in immunotherapy. 4-1BB, also termed 4-1BB and TNFRSF9, was identified in 1989 and originally described as an inducible gene, which was expressed in T lymphocytes (7). 4-1BB exhibited an important effect in various cells and participated in the activation of multiple immune cells, such as CD8 T cells and cytotoxic T lymphocytes (CTL) (8). Emerging evidence has demonstrated that targeting 4-1BB is a uniquely attractive strategy for tumor immunotherapy (9–13). In this review, we discuss the recent advances and prospects of the cancer immunotherapy checkpoint 4-1BB from the aspects of structure, expression, role in tumor microenvironment, development of clinical drugs targeting 4-1BB, and their combination with traditional treatment methods.
Structure of 4-1BB and its ligand
4-1BB, a glycosylated type I membrane protein, contains four cysteine-rich pseudo repeats, which contribute to the formation of a cytoplasmic signaling domain, extracellular domain, and short helical transmembrane domain (7). An elongated structure was generally formed by the extracellular domain of TNFR (variation range: 1 to 4 CRDs). Based on this, antibodies can bind to these molecules through many modalities. Efficient binding of 4-1BB L to 4-1BB results in rapid receptor activation in response to antigenic stimulation. 4-1BBL (TNFSF9), a type II membrane protein of the TNF ligand superfamily, is the binding partner of 4-1BB (14, 15). TNFSF members, typically expressed on the cell membrane, exist in a homotrimeric complex (16–18), which can be divided into three parts: (a) LTα, TNF, RANKL, LIGHT, Apo2L/TRAIL, and CD40L (19, 20); (b) BAFF, APRIL, and EDA; and (c) GITRL, 4-1BBL, and OX40L, among which OX40L and GITRL exhibit a flatter conformation (19, 21). The sequences of 4-1BBL were poorly conserved in human and mouse.
As a member of the tumor necrosis factor superfamily, 4-1BB is mostly expressed on the surface of activated T cells but also on B cells, NK cells, and DC cells (22, 23). 4-1BB is widely distributed on various tumor cells (such as lung tumor cells, and leukemia cells) and has been identified in tissues (such as liver cancer tissue, and tumor vessel walls). Alfaro et al. found that 4-1BB is also expressed in tonsil and lymph node follicular structures. Thence, a comprehensive analysis of its distribution helps uncover potential roles and functions.
Role of 4-1BB in the tumor microenvironment
As shown in Figure 1, both IL-15 and IL-2 can promote the expression of 4-1BB on NK cells, which stimulates the proliferation of NK cells and produces IFN-γ, thus leading to the activation of T cells (24). 4-1BB facilitates the proliferation of CD8+ T cells to produce memory T (Tm) cells (25, 26). Stimulation by 4-1BB will upregulate the expression IL-2 and IFN-γ in CD4+ and CD8+ T cells. However, 4-1BB expresses a controversial effect in T regulatory cells (Treg), which leads to Treg proliferation but alters Treg for cytotoxic or helper effects (27, 28). 4-1BBL inhibits the conversion of CD4+FOXP3- cells to CD4+FOXP+ (29). 4-1BB is also expressed in monocytes, and it promotes upregulation of IL-8 and TNF-α but downregulation of IL-10. The differentiation of monocytes into dendritic cells can be promoted by 4-1BB, and dendritic cells then secrete IL-6 and IL-12 (30). However, 4-1BB stimulation differentiates monocytes into M2 macrophages and accelerates B-cell apoptosis, which also promotes the expression of TNF-α/β in B cells (31).
Figure 1 Role of 4-1BB in the tumor microenvironment.
4-1BB in cancer progression
Through the PI3K/AKT/mTOR pathway, expression of 4-1BB was induced by EBV protein LMP1 to facilitate immune evasion in Hodgkin and Reed–Sternberg cells (32). Low levels of the soluble form of 4-1BBL in patients with AML were associated with better prognosis, especially longer disease-free survival (33). 4-1BB L and 4-1BB were abnormally expressed in tumor cells in hematopoietic malignancies, and their interaction promotes tumor growth in cutaneous T-cell lymphoma (34). Overexpression of 4-1BB on leukemic cells was significantly related to poor prognosis (35). Antitumor activity was enhanced in 4-1BB-knockout mice (36). Similarly, the tumor growth was seriously blocked in 4-1BB knockout mice subcutaneously injected with CT26 cells (37). The findings further proved the critical role of 4-1BB-4-1BBL in tumor development.
4-1BB-targeted drug development
The efficacy of the 4-1BB antibody in preventing cancer in animals has prompted clinical development. The use of monoclonal antibodies to treat cancer has achieved great success over the past few decades, many of which have been under evaluation in different clinical trials, as shown in Table 1.
Table 1 4-1BB modulators in clinical trials.
Urelumab (BMS-663513), the first 4-1BB-targeted therapy to enter clinical trials developed by Bristol–Myers Squibb, is a human IgG4 human monoclonal antibody, which will not inhibit the interaction between 4-1BB with its ligand (38). Preliminary clinical results in phase 1/2 disclosed in 2008 showed encouraging efficacy, but further development was hindered by liver toxicity (39). Urelumab reentered clinical trials in 2012, which was combined with nivolumab, cetuximab, rituximab, and elotuzumab, respectively (12). However, hepatotoxicity of the antibody emerged shortly thereafter, causing the urelumab development program to be shelved. Currently, urelumab, a potent agonist mAb, is still under different clinical trials (Table 1), and strategies to avoid hepatotoxicity and achieve appropriate drug exposure levels are worth investigating. Utomilumab (PF-05082566) is a 4-1BB-humanized IgG2 monoclonal antibody developed by Pfizer (40). Compared with urelumab, it has a higher safety profile and is currently undergoing multiple clinical trials (41).
To reduce the hepatotoxicity of systemic 4-1BB agonists, the development of bispecific antibodies against 4-1BB has been recognized as a viable strategy, and some bispecific antibodies, including GEN1046 (PD-L1/4-1BB) and PRS343 (HER2/4-1BB), are currently being evaluated in different clinical trials (Table 1) (42, 43). ES101 (INBRX-105), a first-in-class tetravalent bispecific antibody targeting PD-L1/4-1BB, originally developed by Inhibrx, was introduced into its Greater China rights by Kewan Pharmaceuticals (44). It contains four domains, and two of them target PD-L1 while the other two target 4-1BB, which can alleviate PD-1/PD-L1-mediated immune checkpoint inhibition. The 4-1BB-binding domain may drive the aggregation of 4-1BB molecules on the surface of T cells, so that 4-1BB-mediated immune activation can be concentrated on T cells near the tumor, effectively reducing the potential off-target toxicity.
In addition to double-antibody drugs, the development of 4-1BB targets has been extended to tertiary and tetraspecific antibodies. NM21-1480 is a monovalent trispecific antibody fragment molecule against PD-L1, 4-1BB, and human serum protein (HSA) (45). NM21-1480 exerts a synergistic effect of 4-1BB agonism and PD-L1 blockade and shows an extended half-life by binding to HSA, thereby reducing the frequency of dosing. GNC-035 is a four-antibody drug targeting PD-L1/CD3/4-1BB/ROR1 while GNC-039 targets PD-L1/4-1BB/CD3/EGFR. In terms of design, both GNC-035 and GNC-039 build symmetrical tetraspecific antibodies based on IgG with three scFvs in series. Among them, PD-L1, 4-1BB, and CD3 are immunoregulatory functions, and the fourth target is tumor antigen. Both drugs are undergoing evaluation in different clinical trials (Table 1).
Future directions
Immunotherapy is known as the fourth cancer treatment after surgery, radiotherapy, and chemotherapy, which has changed the treatment patterns of patients with advanced tumors (46). However, only a minority of cancer patients can benefit from it. Treatment methods such as surgery, chemotherapy, radiotherapy, and targeted therapy can synergize with immunotherapy to enhance the curative effect. Guillerey et al. found that anti-4-1BB mAb combined with chemotherapy could prevent MM relapse and prolong survival in MM mice (47). A study undertaken by Newcomb et al. demonstrated that radiation could synergistically enhance the antitumor effect of anti-4-1BB therapy in a mouse glioma model (48). Moreover, anti-4-1BB mAbs could enhance the efficacy of other antitumor Abs (such as cetuximab, rituximab, and trastuzumab) and exert synergistic effects. Taken together, combination therapy for tumors may also be the future direction of tumor therapy.
Conclusion
To summarize, existing studies support immunotherapies targeting the 4-1BB pathway for the treatment of cancer. In the study, we have summarized the structure of 4-1BB and its ligand as well as the expression in various immune cells and tumor cells. More importantly, we discuss the role of 4-1BB in the microenvironment and tumor progression. Furthermore, the development of drug-targeted 4-1BB was summarized and updated, which exhibited tremendous potential in clinical trials. Although the anti-4-1BB therapy provides hope for cancer treatment, the effectiveness of drugs targeting 4-1BB in clinical antitumor therapy alone or in combination with other antitumor therapies still needs to be investigated in the future.
Author contributions
Y-TW, K-FC and Q-BL conceived the review. All authors contributed to the article and approved the submitted version.
Funding
This work was funded by the National Natural Science Foundation of China (No. 81960663).
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
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Keywords: 4-1BB, immunotherapy, cancer, immune checkpoint inhibitor, clinical trials
Citation: Wang Y-T, Ji W-D, Jiao H-M, Lu A, Chen K-F and Liu Q-B (2022) Targeting 4-1BB for tumor immunotherapy from bench to bedside. Front. Immunol. 13:975926. doi: 10.3389/fimmu.2022.975926
Received: 22 June 2022; Accepted: 29 August 2022;
Published: 16 September 2022.
Edited by:
Xuyao Zhang, Fudan University, ChinaCopyright © 2022 Wang, Ji, Jiao, Lu, Chen and Liu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Qi-Bing Liu, cWliaW5nLmxpdUBoYWlubWMuZWR1LmNu; Kun-Feng Chen, Y2hlbmt1bmZlbmcxOTcyQDEyNi5jb20=
†These authors have contributed equally to this work