The TNF Receptor Superfamily in Co-stimulating and Co-inhibitory Responses

Abstract

Summary Cytokines related to Tumor Necrosis Factor (TNF) provide a communication network essential for coordinating multiple cell types into an effective host defense system against pathogens and malignant cells. The pathways controlled by the TNF superfamily differentiate both innate and adaptive immune cells as well as modulate stromal cells into microenvironments conducive to host defenses. Receptors in the TNFSF family activate diverse cellular functions, from production of type 1 interferons to the modulation of survival of antigen-activated T cells. Here, we focus attention on the subset of TNF superfamily receptors encoded on the immune response locus at Chr 1p36. Recent studies reveal diverse mechanisms utilized by these receptors to either co-stimulate or restrict immune responses. Translation of the fundamental mechanisms of the TNF superfamily is leading to the design of therapeutics that can alter pathogenic processes in several autoimmune diseases or promote immunity to tumors.

The comprehensive molecular landscape of the immunologic co-stimulator B7 and TNFR ligand receptor families in colorectal cancer: immunotherapeutic implications with microsatellite instability

“…Previous studies have demonstrated that B7-H3 participates in both immune stimulatory and inhibitory signals, 20 while TNFSF7 involves in stimulatory signals. 19 Therefore, our findings may provide significant prognostic factors and help to develop new target therapy.…”

“…18,19 However, the gene wide alterations of B7 and TNFR families remain largely unknown in colorectal cancer (CRC). Here, the frequency of B7 and TNFR gene alterations (including mutations, amplifications, and deletions) across 6 studies in colorectal cancer were shown in Figure 1.…”

“…Presently, the co-stimulation pathways mainly involve two major families: the B7 family of immunoglobulins3 and the tumor necrosis factor receptor (TNFR) superfamily. 18,19 The B7 family has 10 reported members, including CD80 (B7-1), CD86 (B7-2), PD-L1 (B7-H1), B7-H2, B7-H3, B7-DC, B7-H4, B7-H5, B7-H6 and B7-H7. 18 These proteins have been proven to regulate both T cell co-stimulatory and co-inhibitory pathways.…”

“…5,20 The TNFR superfamily proteins are expressed by antigen-presenting cells (APC) or tumor cells, functioning as important secondary signals: OX40L (TNFSF4), CD40 (TNFRSF5), CD70 (TNFSF7), CD137L (TNFSF9), HVEM (TNFRSF14), and GITRL (TNFSF18). 19 Previous studies find that many of these molecules are dysregulated and associated with prognosis in different cancer types. 21,22 Moreover, the well-known B7-1 or B7-2/CTLA-4 and PD-L1/PD-1 pathways are promising targets for tumor immune checkpoint therapy.…”

Cytokines and Metabolic Factors Regulate Tumoricidal T-Cell Function During Cancer Immunotherapy

“…T-cell expansion, effector differentiation, migration and survival are potentiated by signals from costimulatory receptors belonging to the TNFR superfamily whose expression are induced following initial antigen stimulation and CD28 costimulation [78][79][80]. The ligands for these receptors are typically expressed on PAMP-activated dendritic cells, and agonists to these costimulatory receptors thus provide critical signals for programming T-cell effector functionality that are otherwise lacking during steady-state antigen presentation [81].…”