TNFR2: A Novel Target for Cancer Immunotherapy

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 (Tregs). 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 Tregs. 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. 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 (Tregs) 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 Tregs 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. 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 (Tregs) 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 Tregs 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. the binding of a ligand or drug on a specific cell-surface receptor, thereby producing a physiological response such as proliferation. the binding of a ligand or drug to a cell-surface receptor that inhibits the physiological response and sometimes involves cell death. a mechanism of cell-mediated immune defense whereby an effector cell of the immune system actively lyses a target cell whose membrane-surface antigens have been bound by specific antibodies. In humans ADCC is usually mediated by IgG. cancer antigen-specific antibodies linked to anticancer drugs for the purpose of targeted delivery to the tumor site. rare, potentially fatal skin and mucous membrane disorders associated with IgG or IgA autoantibodies against distinct adhesion molecules of the epidermis or dermal epidermal basement membrane zone, respectively. a type of biological therapy that stimulates or suppresses the immune system to fight cancer. a type of kidney cancer that originates in the lining of the proximal convoluted tubule; the most common type of kidney cancer in adults, responsible for 90–95% of cases. typically CD8+, with the ability to kill its target directly; also referred to as a Teff. the fragment crystallizable region of an antibody. The Fc is the tail region that cannot bind to an antigen but can mediate nonspecific interaction via Fc receptors and proteins of the complement system to activate the immune system. contains both epitope-recognizing Fab fragments of an antibody but not the Fc portion. acute or chronic inflammation of the pituitary gland resulting in varying degrees of pituitary gland failure. commonly, antibodies that block the interaction between T cells and antigen-presenting cells thereby hampering immune activation. antibodies produced by a single clone of immune cells that bind to a single epitope. genes that promote cell survival and cancer growth. In tumors oncogenes are often highly expressed and mutated, which allows their selective targeting. the expressed protein product of an oncogene. loss of multiple pituitary hormones resulting in secondary endocrine failure such as secondary Addison’s disease, infertility, etc. formerly known as suppressor T cells; an important subset of CD4+ T cells responsible for maintaining tolerance to self-antigens and suppressing the deleterious effects of T helper cells. a subset of white blood cells that matures in the thymus and plays an important role in cell-mediated immunity. TNF, the TNFR, and their related superfamily of trimeric ligands and corresponding receptors are transmembrane proteins that play important roles in immune function, cell proliferation, morphogenesis, and cell death.