Role for CD40L in the Therapy of Human Cancer

CD40L-CD40 interaction is central to the control of thymusdependent humoral immunity and cell mediated immune responses. CD40, a member of the tumor necrosis factor receptor (TNFR) family, has been found on the surface of B lymphocytes, monocytes, hematopoietic progenitors, dendritic cells (DCs), endothelial cells, epithelial cells and so on. Its natural ligand (CD40 ligand, CD40L), CD154, a member of the tumor necrosis factor (TNF) family, is mainly expressed on activated CD4 + T lymphocytes. A direct growth-inhibitory effect can be found when ligated CD40 is on human breast, ovarian, cervical, bladder, non-small cell lung, and squamous epithelial carcinoma cells. This effect is related to the induction of cell cycle blockage and/or apoptosis. CD40L induces phenotypic and functional maturation of DCs, and can increase tumor immunogenicity through up-regulation of costimulatory molecular expression and cytokine production by epithelial cancer cells. As a result, CD40L can enhance tumor rejection immune responses. Furthermore, by means of a “bystander effect”, even CD40-negative tumor subsets can be eliminated by activated tumor-reactive cytotoxic T lymphocytes(CTL). This review summarizes recent findings on CD40L recombinant protein and gene therapy-based tumor treatment approaches.