Phenotypic screening reveals TNFR2 as a promising target for cancer immunotherapy

Williams, G. L.; Mistry, Bina; Guillard, Sandrine; Ulrichsen, Jane Coates; Sandercock, Alan M.; Wang, Jun; González-Muñoz, Andrea; Parmentier, Julie; Black, Chelsea M.; Soden, Jo; Freeth, Jim; Jovanović, Jelena; Leyland, Rebecca; Al‐Lamki, Rafia S.; Leishman, Andrew J.; Rust, Steve; Stewart, Ross; Jermutus, Lutz; Bradley, John R.; Bedian, Vahe; Valge-Archer, Viia; Minter, Ralph; Wilkinson, Robert W.

doi:10.18632/oncotarget.11943

Cited by 47 publications

(50 citation statements)

References 55 publications

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“…However, the level of TNFR2 expressed by Teffs is much lower than its expression on Tregs ( 6 , 9 , 23 , 28 ). This may explain why TNFR2 antibody mimetics preferentially bind to Tregs ( 21 ). Nevertheless, TNFR2-targeting agents on the function of Teffs should be carefully evaluated in the future study.…”

Section: Discussionmentioning

confidence: 99%

Modulation of Regulatory T Cell Activity by TNF Receptor Type II-Targeting Pharmacological Agents

Zou

et al. 2018

Front. Immunol.

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There is now compelling evidence that tumor necrosis factor (TNF)–TNF receptor type II (TNFR2) interaction plays a decisive role in the activation, expansion, and phenotypical stability of suppressive CD4+Foxp3+ regulatory T cells (Tregs). In an effort to translate this basic research finding into a therapeutic benefit, a number of agonistic or antagonistic TNFR2-targeting biological agents with the capacity to activate or inhibit Treg activity have been developed and studied. Recent studies also show that thalidomide analogs, cyclophosphamide, and other small molecules are able to act on TNFR2, resulting in the elimination of TNFR2-expressing Tregs. In contrast, pharmacological agents, such as vitamin D3 and adalimumab, were reported to induce the expansion of Tregs by promoting the interaction of transmembrane TNF (tmTNF) with TNFR2. These studies clearly show that TNFR2-targeting pharmacological agents represent an effective approach to modulating the function of Tregs and thus may be useful in the treatment of major human diseases such as autoimmune disorders, graft-versus-host disease (GVHD), and cancer. In this review, we will summarize and discuss the latest progress in the study of TNFR2-targeting pharmacological agents and their therapeutic potential based on upregulation or downregulation of Treg activity.

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Section: Discussionmentioning

confidence: 99%

Modulation of Regulatory T Cell Activity by TNF Receptor Type II-Targeting Pharmacological Agents

Zou

et al. 2018

Front. Immunol.

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“…Activation of TNFR2 on T con cells can lead to enhanced tumoricidal effects ( 81 ). TNFR2 on T con cells also activates those effector T cells making them resistant to T cell-mediated suppression ( 82 ).…”

Section: Tnfr2 Promoting Tumorigenesis and Progressionmentioning

confidence: 99%

TNF Receptor 2 Makes Tumor Necrosis Factor a Friend of Tumors

Sheng

Qin

2018

Front. Immunol.

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Tumor necrosis factor (TNF) is widely accepted as a tumor-suppressive cytokine via its ubiquitous receptor TNF receptor 1 (TNFR1). The other receptor, TNFR2, is not only expressed on some tumor cells but also on suppressive immune cells, including regulatory T cells and myeloid-derived suppressor cells. In contrast to TNFR1, TNFR2 diverts the tumor-inhibiting TNF into a tumor-advocating factor. TNFR2 directly promotes the proliferation of some kinds of tumor cells. Also activating immunosuppressive cells, it supports immune escape and tumor development. Hence, TNFR2 may represent a potential target of cancer therapy. Here, we focus on expression and role of TNFR2 in the tumor microenvironment. We summarize the recent progress in understanding how TNFR2-dependent mechanisms promote carcinogenesis and tumor growth and discuss the potential value of TNFR2 in cancer treatment.

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“…Antagonism of TNFR2, by contrast, kills target cells through inactivation of NF‐kB signaling and the stabilization of strong hexagonal networks of receptors with poor signaling activity 4,9,10 . In most human tumors, every Treg in the TME expresses newly made and high‐density TNFR2 7 . Human cancers with high TNFR2 expression in the TME have poor prognosis and secrete into the serum soluble TNF (sTNFR2), a prognostic marker 11–15 .…”

Section: Introductionmentioning

confidence: 99%

“…Human cancers with high TNFR2 expression in the TME have poor prognosis and secrete into the serum soluble TNF (sTNFR2), a prognostic marker 11–15 . The most suppressive subset of Tregs highly express TNFR2 in the TME of both humans and rodents 5–7 . Therefore, the central role of TNFR2 in diseases of immune dysregulation, such as autoimmunity and cancer, is established 1–5,10 …”

Section: Introductionmentioning

confidence: 99%

Optimizing TNFR2 antagonism for immunotherapy with tumor microenvironment specificity

Yang

Trần

Torrey

et al. 2020

Journal of Leukocyte Biology

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Most approved cancer immunotherapies lack T‐regulatory (Treg) or tumor specificity. TNF receptor 2 (TNFR2) antibody antagonism is emerging as an attractive immunotherapy due to its tumor microenvironment (TME) specificity. Here we show that the human TNFR2 receptor is overexpressed on both human tumor cells and on human tumor‐residing Tregs, but negligibly expressed on beneficial T effectors (Teffs). Further, we found widespread, if variable, TNFR2 expression on 788 human tumor cell lines from diverse cancer tissues. These findings provided strong rationale for developing a targeted immunotherapy using a TNFR2 antibody antagonist. We designed a novel, human‐directed TNFR2 antibody antagonist and tested it for function using three cell‐based TME assays. The antagonist showed TME specificity by killing of TNFR2‐expressing tumor cells and Tregs, but sparing Teffs, which proliferated. However, the antagonist shuffled between five isoforms, only one of which showed the desirable function. We designed and tested several new chimeric human versions of the antagonist, finding that the IgG2 isotype functioned better than the IgG1 isotype. To further improve function, we introduced targeted mutations to its amino acid sequence to stabilize the natural variability of the IgG2 isotype's hinge. Altogether, our findings suggest that optimal TNFR2 antagonists are of the human IgG2 isotype, have hinge stabilization, and have wide separation of antibody arms to bind to newly synthesized TNFR2 on rapidly growing tumor cells. Antagonistic antibodies with these characteristics, when bound to TNFR2, can form a nonsignaling cell surface dimer that functions with high TME specificity.

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Phenotypic screening reveals TNFR2 as a promising target for cancer immunotherapy

Cited by 47 publications

References 55 publications

Modulation of Regulatory T Cell Activity by TNF Receptor Type II-Targeting Pharmacological Agents

Modulation of Regulatory T Cell Activity by TNF Receptor Type II-Targeting Pharmacological Agents

TNF Receptor 2 Makes Tumor Necrosis Factor a Friend of Tumors

Optimizing TNFR2 antagonism for immunotherapy with tumor microenvironment specificity

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