Targeting TNFR2 in Cancer: All Roads Lead to Rome

Bai, Jingchao; Ding, Bowen; Li, Hui

doi:10.3389/fimmu.2022.844931

Cited by 18 publications

(20 citation statements)

References 93 publications

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“…Tumor necrosis factor receptor 2 (TNFR2), the receptor of TNF, has been found that is highly expressed in humans and mouse Tregs, especially on eTregs. 81 , 82 , 83 , 84 , 85 Interestingly, the interaction of TNF with TNFR2 promotes suppressive function and phenotypical stability of Tregs. 86 , 87 Based on this interaction, Nie et al.…”

Section: Treg Subsets In Tumor Immunitymentioning

confidence: 99%

Different subpopulations of regulatory T cells in human autoimmune disease, transplantation, and tumor immunity

Jiang

Zhu

Wang

et al. 2022

MedComm

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CD4 + CD25 + regulatory T cells (Tregs), a subpopulation of naturally CD4 + T cells that characteristically express transcription factor Forkhead box P3 (FOXP3), play a pivotal role in the maintenance of immune homeostasis and the prevention of autoimmunity. With the development of biological technology, the understanding of plasticity and stability of Tregs has been further developed. Recent studies have suggested that human Tregs are functionally and phenotypically diverse. The functions and mechanisms of different phenotypes of Tregs in different disease settings, such as tumor microenvironment, autoimmune diseases, and transplantation, have gradually become hot spots of immunology research that arouse extensive attention. Among the complex functions, CD4 + CD25 + FOXP3 + Tregs possess a potent immunosuppressive capacity and can produce various cytokines, such as IL‐2, IL‐10, and TGF‐β, to regulate immune homeostasis. They can alleviate the progression of diseases by resisting inflammatory immune responses, whereas promoting the poor prognosis of diseases by helping cells evade immune surveillance or suppressing effector T cells activity. Therefore, methods for targeting Tregs to regulate their functions in the immune microenvironment, such as depleting them to strengthen tumor immunity or expanding them to treat immunological diseases, need to be developed. Here, we discuss that different subpopulations of Tregs are essential for the development of immunotherapeutic strategies involving Tregs in human diseases.

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Section: Treg Subsets In Tumor Immunitymentioning

confidence: 99%

Different subpopulations of regulatory T cells in human autoimmune disease, transplantation, and tumor immunity

Jiang

Zhu

Wang

et al. 2022

MedComm

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“…In vivo , TNFR2-overexpressing cancer cells promote the accumulation of TNFR2 + Tregs in the draining lymph nodes and increase the levels of sTNFR2 in the circulation ( 45 ). These studies suggest that elevated sTNFR2 could be an indicator of cancer ( 10 , 12 , 13 ). Therefore, the circulating sTNFR2 could potentially lend itself as a novel diagnostic biomarker to detect the presence of cancer.…”

Section: Introductionmentioning

confidence: 94%

“…TNFR2 is also highly expressed in immune cells, which could be associated with tumorigenesis and tumor growth or conversely tumor controls ( 10 , 12 , 13 ). This protein however has been shown to be broadly expressed in the repertoire of immunosuppressive cells present on tumors and tumor microenvironments promoting pro-tumor activity ( 9 ).…”

Section: Introductionmentioning

confidence: 99%

Elevation of circulating TNF receptor 2 in cancer: A systematic meta-analysis for its potential as a diagnostic cancer biomarker

et al. 2022

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High Tumor Necrosis Factor Receptor 2 (TNFR2) expression is characteristic of diverse malignant cells during tumorigenesis. The protein is also expressed by many immunosuppressive cells during cancer development, allowing cancer immune escape. A growing body of evidence further suggests a correlation between the circulating form of this protein and cancer development. Here we conducted a systematic meta-analysis of cancer studies published up until 1st October 2022, in which the circulating soluble TNFR2 (sTNFR2) concentrations in patients with cancers were recorded and their association with cancer risk was assessed. Of the 14,615 identified articles, 44 studies provided data on the correlation between cancer risk and the level of circulating sTNFR2. The pooled means comparison showed a consistently significant increase in the levels of sTNFR2 in diverse cancers when compared to healthy controls. These included colorectal cancer, ovarian cancer, breast cancer, non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, lung cancer, hepatocarcinoma, and glioblastoma. In a random-effect meta-analysis, the cancer-specific odd ratios (OR) showed significant correlations between increased circulating sTNFR2 levels and the risk of colorectal cancer, non-Hodgkin’s lymphoma, and hepatocarcinoma at 1.59 (95% CI:1.20-2.11), 1.98 (95% CI:1.49-2.64) and 4.32 (95% CI:2.25-8.31) respectively. The overall result showed an association between circulating levels of sTNFR2 and the risk of developing cancer at 1.76 (95% CI:1.53-2.02). This meta-analysis supports sTNFR2 as a potential diagnostic biomarker for cancer, albeit with different predictive strengths for different cancer types. This is consistent with a potential key role for TNFR2 involvement in cancer development.

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“…Aggregated TNFR2 increases the density of receptor-associated intracellular proteins, triggering the activation of downstream canonical and noncanonical NF-κB pathways (1, 5,6). TNFR2 is primarily expressed in a subset of T cells, including regulatory T cells (Tregs) (7)(8)(9)(10), and TNFR2-mediated intracellular signaling expands Tregs, inducing cancer cell proliferation. Therefore, anti-TNFR2 antagonists are promising as a new type of immune checkpoint inhibitor to enhance the immune response in patients with cancer (9)(10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

“…TNFR2 is primarily expressed in a subset of T cells, including regulatory T cells (Tregs) (7)(8)(9)(10), and TNFR2-mediated intracellular signaling expands Tregs, inducing cancer cell proliferation. Therefore, anti-TNFR2 antagonists are promising as a new type of immune checkpoint inhibitor to enhance the immune response in patients with cancer (9)(10)(11)(12). In contrast, anti-TNFR2 signal-inducing antibodies (agonists) are pursued as therapeutic strategies to expand Tregs in autoimmunity, organ transplant rejection, and graft-versus-host disease.…”

Section: Introductionmentioning

confidence: 99%

Development of a 1:1-binding biparatopic anti-TNFR2 antagonist by epitope selection

Akiba

Fujita

Ise

et al. 2022

Preprint

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Conventional bivalent antibodies against cell surface receptors often initiate unwanted signal transduction by crosslinking two antigen molecules. Biparatopic antibodies (BpAbs) bind to two different epitopes on the same antigen, thus altering crosslinking ability. In this study, we developed BpAbs against tumor necrosis factor receptor 2 (TNFR2), which is an attractive immune checkpoint target. Using different pairs of variable regions specific to topographically distinct TNFR2 epitopes, we successfully regulated the size of BpAb-TNFR2 immunocomplexes to result in controlled agonistic activities. One particular antagonist BpAb bound TNFR2 in 1:1 ratio without unwanted signal transduction, with its structural basis revealed by cryo-electron microscopy. This antagonist suppressed the proliferation of regulatory T cells expressing TNFR2. Therefore, the BpAb format would be useful in designing specific and distinct antibody functions.

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Targeting TNFR2 in Cancer: All Roads Lead to Rome

Cited by 18 publications

References 93 publications

Different subpopulations of regulatory T cells in human autoimmune disease, transplantation, and tumor immunity

Different subpopulations of regulatory T cells in human autoimmune disease, transplantation, and tumor immunity

Elevation of circulating TNF receptor 2 in cancer: A systematic meta-analysis for its potential as a diagnostic cancer biomarker

Development of a 1:1-binding biparatopic anti-TNFR2 antagonist by epitope selection

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