Tumor Necrosis Factor Receptor 2 (TNFR2): An Emerging Target in Cancer Therapy

Abstract

Despite the great success of TNF blockers in the treatment of autoimmune diseases and the identification of TNF as a factor that influences the development of tumors in many ways, the role of TNFR2 in tumor biology and its potential suitability as a therapeutic target in cancer therapy have long been underestimated. This has been fundamentally changed with the identification of TNFR2 as a regulatory T-cell (Treg)-stimulating factor and the general clinical breakthrough of immunotherapeutic approaches. However, considering TNFR2 as a sole immunosuppressive factor in the tumor microenvironment does not go far enough. TNFR2 can also co-stimulate CD8+ T-cells, sensitize some immune and tumor cells to the cytotoxic effects of TNFR1 and/or acts as an oncogene. In view of the wide range of cancer-associated TNFR2 activities, it is not surprising that both antagonists and agonists of TNFR2 are considered for tumor therapy and have indeed shown overwhelming anti-tumor activity in preclinical studies. Based on a brief summary of TNFR2 signaling and the immunoregulatory functions of TNFR2, we discuss here the main preclinical findings and insights gained with TNFR2 agonists and antagonists. In particular, we address the question of which TNFR2-associated molecular and cellular mechanisms underlie the observed anti-tumoral activities of TNFR2 agonists and antagonists.

Loss of tumor necrosis factor (TNF)‐receptor 1 and TNF‐receptor 2 partially replicate effects of TNF deficiency on dendritic spines of granule cells in mouse dentate gyrus

“…TNF‐R2 is activated by membrane‐bound TNF and far more selectively expressed than TNF‐R1 (Gough & Myles, 2020). Most of our knowledge on TNF‐R2 stems from cell culture experiments, and non‐neuronal cells and TNF‐R2 have been proposed as a possible target for cancer therapy (Medler et al., 2022). However, TNF‐R2 is also expressed by neurons (Becker et al., 2015; Gough & Myles, 2020), and functional data suggest that TNF could use TNF‐R2 to regulate synaptic strength (Becker et al., 2015; He et al., 2012).…”

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

“…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).…”

“…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.…”

“…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. (9,10,(13)(14)(15). Bivalency of conventional antibody (cIgG) could produce dimer formation-related unwanted cellular responses (16).…”

“…In contrast, anti-TNFR2 signal-inducing antibodies (agonists) are pursued as therapeutic strategies to expand T regs in autoimmunity, organ transplant rejection, and graft-versus-host disease. ( 9,10,13-15 ).…”