TNFR2: A Novel Target for Cancer Immunotherapy. Issue 11 (November 2017) - Vanamee, Éva S.
Abstract : Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy but exhibit variable efficacy and relapse and can induce autoimmunity. Tumor necrosis factor (TNF) receptor 2 (TNFR2) is a signaling molecule found on the surface of a subset of potent regulatory T cells (Treg s) that can activate the proliferation of these cells through nuclear factor kappa B (NF-κB). TNFR2 is also abundantly expressed on the surface of many human tumors. We propose that blocking TNFR2 might target abundant TNFR2 + tumor-infiltrating Treg s and directly kill TNFR2-expressing tumors. We also posit that TNFR2 inhibitors might potentially constitute safer and more targeted alternatives to ICI cancer treatment because the expression of TNFR2 on immune cells, concentrated in the tumor microenvironment of various cancers, appears to be more selective than that of checkpoint molecules. Trends: Tumor antigens have been successfully targeted by monoclonal antibodies, including epidermal growth factor, ERBB2, vascular endothelial growth factor, cytotoxic T lymphocyte antigen 4, CD20, CD30, CD52, and programmed cell death protein 1. Recently developed immune checkpoint inhibitors have shown great promise in eliminating previously hard-to-treat tumors but can cause unwanted autoimmune side effects. In addition, they may have a desirable effect in only approximately 30% of patients. Cancer treatment strategies often aim to target immunosuppressive regulatory T cells (Treg s). Tumor necrosis factor (TNF) receptor 2 (TNFR2) has been deemed both an oncogene and an inducer of Treg expansion. TNFR2 antagonism can boost antitumor immune responses and block the expansion of Treg s. TNFR2 has limited expression across cell types, providing a rationale for its inhibition as a more selective targeted therapy with potentially fewer side effects. Cancer therapies are increasingly relying on combination approaches to increase efficacy. Due to the critical role of TNF superfamily (TNFSF) pathways in immune surveillance and cell proliferation and death, therapies targeting TNFSF receptors might play an important role in putative combination therapies.