CD40L belongs to tumor necrosis factor,TNF. Type II transmembrane proteins in the superfamily are expressed on the surface of activated CD 4T cells, B cells and cancer cells. The process of CD40/CD40L signaling pathway is that CD40L receptor molecules are expressed on the cell surface in the form of multiple subunit combinations and belong to the TNF receptor superfamily. The role of CD40/CD40L pathway in inducing immunity, inflammation and hemostasis has been clarified and the relationship between this signaling pathway and tumor-related diseases is still under further study. CD40L inhibits tumor progression not only by forming recombinant ligands with vaccines, but also by inhibiting the release of platelet-derived CD40L. The following is an overview of the multiple relationships between CD40/CD40L and tumor-related diseases.
The mechanism of TNF receptor superfamily on immune upregulation is different from that of B7/CD28 immune costimulatory interaction. Among them, the more well-known member is CD27, specific expression in lymphocytes. And the CD27/CD70 signaling pathway is quite different from others. When activated, CD27 is highly expressed on the cell surface. CD27 signals are restricted by the expression of ligand CD70, which is activated by antigen receptors in T cells, B cells and dendritic cells. CD27 / CD70 signal can promote the clone expansion and survival of T cells, promote the differentiation of T cells, enhance the activation and function of B cells and NK cells.
In transgenic mice, the persistent expression of CD70 can activate CD27/CD70 signaling pathway, up-regulate effector T cells and prevent tumor development. In preclinical mice with normal immune function, CD27 agonist therapy can also prevent tumor formation and development. Varlilumab is an all-human monoclonal antibody targeting CD27. At present, it is in the phase of phase two clinical study of treating malignant melanoma and solid tumor, one or two stage clinical study of treating renal cell carcinoma and one stage clinical trial of treating malignant tumor of blood system and prostate cancer. The drug has been treated with milk. The clinical phase I trial of adenocarcinoma and ovarian cancer has been terminated. For the treatment of CD70, three antibody-coupled drugs and one monoclonal antibody are currently in clinical study.
4-1BB, also known as CD137, and OX40, is a member of the tumor necrosis factor (TNF) receptor family, which is encoded by a member of the tumor necrosis factor receptor superfamily 9 (TNFRSF9). The 4-1BB/4-1BBL signaling pathway is very interesting. Human 4-1BB is located on chromosome 1p36 and is 255aa in length. It contains 17aa signal peptide, extracellular domain of 169aa, transmembrane 27aa region (p. 187-213) and intracellular region of 42aa. Mouse 4-1BB is located at 75.5 cM on chromosome 4 of mice and is approximately 60% similar to human 4-1BB.
4-1BB is an inducible costimulatory receptor expressed on activated CD4 and CD8 T cells, NKT, NK cells, DC, macrophages, eosinophils, neutrophils and mast cells and Tregs. Except for the constitutive expression of 4-1BB on APC and Foxp3 Tregs, in most cases, 4-1BB was induced on the surface of activated cells.
Several studies using 4-1BB-r-knockout mice have found that 4-1BB plays an important role in maintaining immune homeostasis, and it is important to fight tumor immune memory. The importance of the 4-1BB pathway has also been confirmed in CAR-T cell therapy approved by the U.S. Drug Administration.
