CD40 and CD40L Pathway

CD40 and CD40L Pathway

CD40 is a member of the tumor necrosis factor receptor (TNFR) superfamily, which is expressed on the surface of a variety of cell types such as macrophages, B cells, dendritic cells (DCs), microglia, endothelial cells, and epithelial cells. CD40L, its ligand, is a type II transmembrane protein belonging to the TNF superfamily. CD40L is transiently expressed on the surface of activated CD4+ T cells but can also be up-regulated on other cell types in the context of autoimmune disease.

The CD40/CD40L interaction results in the movement of CD40 into cholesterol-rich membrane microdomains and the binding of TNFR-associated factors (TRAFs) to its cytoplasmic tail. Specific TRAF molecules are associated with overlapping and distinct CD40-mediated functions. CD40 directly binds TRAF2, TRAF3, TRAF5, and TRAF6, and indirectly associates with TRAF1. These interactions result in activation of mitogen and stress-activated protein kinase (MAPK/SAPK) cascades, transcription factor activation, cytokine secretion, proliferation and differentiation of B cells into Ig-secreting plasma cells, and humoral memory establishment.

The CD40 signaling pathway. Fig.1 The CD40 signaling pathway. (Vonderheide, 2007)

Therapies Targeting CD40/CD40L Pathway

Studies have shown that CD40 is widely expressed on human melanoma, prostate, lung cancers, as well as in carcinomas of the nasopharynx, ovary, bladder, and cervix. CD40/CD40L is critical for developing protective anti-tumor immunity, and CD40 can be a cancer-associated target in antibody-based therapies. Over the past years, different strategies have been explored to prolong graft survival mediated by anti-CD40L antibodies. Many approaches make full use of blocking antibodies to other costimulatory molecules, such as OX40 and CD28, or agonistic antibodies for coinhibitory molecules, such as CTLA-4. The roles of newer members in the co-stimulation family have also been targeted in combination with anti-CD40L, such as PD1/PD-L1 and the ICOS.

So far, three main rationales have been used in the development of clinical phase I studies that target the CD40 pathway.

  1. CD40 can act as a tumor-associated antigen to which a cytotoxic antibody can be targeted.
  2. CD40 engagement by an antibody can transduce a pro-apoptotic signal to a tumor cell to facilitate its death.
  3. An agonistic anti-CD40 antibody can enhance immunity to the tumor and facilitate the development of therapeutic immunity.

Clinical Trials

Given the broad spectrum of impact of CD40 signaling on the immune response and its potential role in various diseases, several molecules targeting the CD40 and CD40L pathway have been generated and evaluated in clinical settings. Therapeutics that target the CD40-CD40L axis can broadly modulate a multitude of responses influenced by this pathway, including antibody-mediated and cellular immune processes. It will be important for future studies to explore the impact of CD40-CD40L blocking agents on both the non-humoral and humoral aspects of CD40 biology.

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  1. Vonderheide, R. H. Prospect of targeting the CD40 pathway for cancer therapy. Clinical Cancer Research. 2007, 13(4): 1083-1088.

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