CD40 / TNFRSF5 is a member of the tumor necrosis factor (TNF) superfamily and is highly expressed on nearly all B-cell malignancies. It is well established that interaction of CD40 / TNFRSF5 with its natural ligand CD40L / CD154 / TNFSF5 can rescue tumor cells from apoptosis, prolong survival and augment proliferation. CD40L / CD154 / TNFSF5 is provided either by the microenvironment, i.e. infiltrating T-cells, dendritic cells and mast cells, and/or by the tumor itself, i.e. coexpression of CD40 / TNFRSF5 and CD40L / CD154 / TNFSF5 on lymphoma cells as well as secretion of biologically active, soluble CD40L / CD154 / TNFSF5.
Numerous studies have indicated that CD40 & CD40L immune checkpoint pathway is a major regulating factor of immune responses. Briefly, CD40 & CD40L immune checkpoint pathway affects the immune system in the following four ways (5): (1) CD40 & CD40L immune checkpoint pathway "activates" or "matures" antigen-presenting cells (APCs, mainly macrophages and dendritic cells) to express co-stimulatory molecules including B7 (CD80 and CD86, both ligands for CD28), ICAM-1 (CD54), and CD44. These co-stimulatory signals are needed for T cells to become fully activated, rather than anergic, after T cell receptor (TCR)-stimulation. (2) CD40 & CD40L immune checkpoint pathway induces macrophages and dendritic cells to make interleukin-12 (IL-12), IL-18, and other cytokines. In an immunological response, CD40L / CD154 / TNFSF5 is the primary stimulus for IL-12 production (in the absence of microbial invasion). IL-12 and IL-18 stimulate NK cells for interferon-γ (IFN-γ) production. IL-12 causes CD4+ T cells to differentiate into type 1 helper T cells (Th1) that mediate delayed-type hypersensitivity responses. (3) CD40L / CD154 / TNFSF5-expressing CD4+ T cells are generally required for the generation of cytotoxic T lymphocytes (CTLs) against tumors and virus-infected cells. As in CD4+ T cell activation, CD40 & CD40L immune checkpoint pathway activates APCs to express the co-stimulatory molecules needed to fully activate ("cross-prime") CTLs already responding to antigen/MHC class I complexes. (4) CD40 & CD40L immune checkpoint pathway promotes the differentiation of activated B cells and, with few exceptions, is required for the "class switch" from IgM to IgG production.
Richard S. Kornbluth et al. The emerging role of CD40 ligand in HIV infection. Journal of Leukocyte Biology. 2000 ; 68:373-382.