Role of 4-1BB:4-1BB ligand in cancer immunotherapy

Abstract

The activation of T cells plays a central role in antitumor immunity. In order to activate naïve T cells, two key signals are required. Signal one is provided through the T-cell receptor (TCR) while signal two is that of costimulation. The CD28:B7 molecules are one of the best-studied costimulatory pathways, thought to be the main mechanism through which primary T-cell stimulation occurs. However, a number of molecules have been identified which serve to amplify and diversify the T-cell response, following initial Tcell activation. These include the more recently described 4-1BB:4-1BB ligand (4-1BBL) molecules. 4-1BB:4-1BBL are a member of the TNFR:TNF ligand family, which are expressed on T cells and antigen-presenting cells (APCs), respectively. Therapies utilizing the 4-1BB:4-1BBL signaling pathway have been shown to have antitumor effects in a number of model systems. In this paper, we focus on the 4-1BB:4-1BBL costimulatory molecules. In particular, we will describe the structure and function of the 4-1BB molecule, its receptor and how 4-1BB:4-1BBL costimulation has and may be used for the immunotherapy of cancer.

Immobilized MHC class I chain-related protein A synergizes with IL-15 and soluble 4-1BB ligand to expand NK cells with high cytotoxicity ex vivo

“…6 IL-15 is essential for the development and function of NK cells. 7 Coculture of NK cells with K562 cells ectopically coexpressing 4-1BB ligand (4-1BBL) and membrane-bound IL-15 effectively promotes the expansion of NK cells in vitro and mediates their cytotoxicity against some leukemia cells.…”

Combining Antibody-Directed Presentation of IL-15 and 4-1BBL in a Trifunctional Fusion Protein for Cancer Immunotherapy

“…Thus, IL-15 holds great potential for combination therapies. 4-1BB is a costimulatory member of the TNF receptor superfamily (TNFR-SF) that is upregulated on activated T cells and NK cells (19). Costimulation by 4-1BBL/4-1BB interaction is fundamentally involved in the proliferation, differentiation, and survival of CD8 þ T cells, therefore thought to play an important role in potentiating cytotoxic T-cell immune responses (20).…”

Establishment and Characterization of a Cell Based Artificial Antigen-Presenting Cell for Expansion and Activation of CD8+ T Cells Ex Vivo

“…In addition, K32/CD3/28 cells promoted the expansion of CD4 + T cells whereas failed to support long-term growth of CD8 + T cells. 4-1BB stimulation preferentially activated CD8 + T cells in vitro and amplified generation of CTL responses in vivo (28,29). It was shown that the addition of 4-1BB co-stimulation not only could promote CD8 + T cell proliferation, but also overcome activation-induced non-responsiveness to increase IL-2 and Bcl-xL expression and survival of CD8 + T cells (3).…”