Multifunctional CD40L: pro- and anti-neoplastic activity

Abstract

The CD40 ligand is a type I transmembrane protein that belongs to a tumor necrosis factor (TNF) superfamily. It is present not only on the surface of activated CD4+ T cells, B cells, blood platelets, monocytes, and natural killer (NK) cells but also on cancer cells. The receptor for ligand is constitutively expressed on cells, TNF family protein: CD40. The role of the CD40/CD40L pathway in the induction of body immunity, in inflammation, or in hemostasis has been well documented, whereas its involvement in neoplastic disease is still under investigation. CD40L ligand may potentiate apoptosis of tumor cells by activation of nuclear factor-κB (NF-κB), AP-1, CD95, or caspase-depended pathways and stimulate host immunity to defend against cancer. Although CD40L has a major contribution to anti-cancer activity, many reports point at its ambivalent nature. CD40L enhance release of strongly pro-angiogenic factor, vascular endothelial growth factor (VEGF), and activator of coagulation, TF, the level of which is correlated with tumor metastasis. CD40L involvement in the inhibition of tumor progression has led to the emergence of not only therapy using recombinant forms of the ligand and vaccines in the treatment of cancer but also therapy consisting of inhibiting platelets-main source of CD40L. This article is a review of studies on the ambivalent role of CD40L in neoplastic diseases.

Fig. 1

This figure illustrates some of the mechanisms by which CD40L can influence on different cell functions and the processes by which these altered cells can impact on host immunity in neoplastic diseases. CD40L is present as a membrane-bound form (mCD40L), present first of all on T lymphocytes (CD4+, CD8+, iNKTc, and NKc), and as a soluble form (sCD40L) derived primarily from active platelets. Interaction of the ligand with the receptor (CD40) may not only potentiate the anti-tumor immunity but also promote the development of cancer. The binding of CD40L with a receptor on dendritic cells (DC) leads to the expression of co-stimulatory molecules necessary for the correct antigen presentation and protects DC against apoptosis induced by factors derived from tumor cells (TC). Moreover, CD40L/CD40 interaction enhances the proliferation and maturation of lymphocytes B (B cells) and the production of antibodies against the tumor. mCD40L present on various cells induces apoptosis of tumor cells via the TRAF-JNK/AP-1-caspase-9/caspase-3 pathway. On the other hand, the activation of endothelial cells (EC) may result in enhance TF pro-coagulant activity and high expression of VEGF, main mediator of tumor angiogenesis