Interleukin-15 receptor, Tumor necrosis factor receptor superfamily member 9, and T-cell-specific surface glycoprotein CD28 (IL-15R/4-1BB/CD28)

The combination of Interleukin-15 receptor (IL-15R), 4-1BB (CD137), and CD28 represents a critical triad of signaling pathways used to modulate and enhance T-cell-mediated immunity. CD28 is the primary costimulatory receptor required for initial T-cell activation and metabolic reprogramming (UniProt: P16284). 4-1BB, a member of the tumor necrosis factor receptor superfamily, provides secondary signals that promote long-term survival, memory differentiation, and metabolic fitness (UniProt: Q07011). IL-15R signaling, typically through the IL-15/IL-15Rα complex, further supports the homeostatic proliferation and persistence of CD8+ effector T-cells and Natural Killer (NK) cells (UniProt: P40933). In modern oncology, these three components are frequently integrated into the design of chimeric antigen receptor (CAR) T-cells to overcome the immunosuppressive tumor microenvironment (PMID: 30635554). For instance, second and third-generation CARs utilize CD28 and/or 4-1BB endodomains to drive potent anti-tumor responses, while IL-15 is often co-expressed to enhance cell longevity (PMID: 30104341). Drugs targeting these molecules, such as the IL-15 superagonist Nogapendekin alfa inbakicept (N-803) and 4-1BB agonists like Urelumab, aim to boost anti-tumor efficacy in both liquid and solid tumors. However, therapeutic application is challenged by safety concerns such as cytokine release syndrome (CRS) and potential hepatotoxicity (PMID: 29367878).

Other names

CD137TNFRSF9ILACD122CD132IL-15RATp44CD28

Agonism of costimulatory (CD28, 4-1BB) and cytokine (IL-15R) signaling pathways to enhance T-cell effector function, metabolic fitness, and long-term persistence.