CD40

Official Full Name

CD40 molecule

Organism

Homo sapiens

GeneID

958

Background

This gene is a member of the TNF-receptor superfamily. The encoded protein is a receptor on antigen-presenting cells of the immune system and is essential for mediating a broad variety of immune and inflammatory responses including T cell-dependent immunoglobulin class switching, memory B cell development, and germinal center formation. AT-hook transcription factor AKNA is reported to coordinately regulate the expression of this receptor and its ligand, which may be important for homotypic cell interactions. Adaptor protein TNFR2 interacts with this receptor and serves as a mediator of the signal transduction. The interaction of this receptor and its ligand is found to be necessary for amyloid-beta-induced microglial activation, and thus is thought to be an early event in Alzheimer disease pathogenesis. Mutations affecting this gene are the cause of autosomal recessive hyper-IgM immunodeficiency type 3 (HIGM3). Multiple alternatively spliced transcript variants of this gene encoding distinct isoforms have been reported. [provided by RefSeq, Nov 2014]

Synonyms

p50; Bp50; CDW40; TNFRSF5;

Bio Chemical Class

Cytokine receptor

Protein Sequence

MVRLPLQCVLWGCLLTAVHPEPPTACREKQYLINSQCCSLCQPGQKLVSDCTEFTETECLPCGESEFLDTWNRETHCHQHKYCDPNLGLRVQQKGTSETDTICTCEEGWHCTSEACESCVLHRSCSPGFGVKQIATGVSDTICEPCPVGFFSNVSSAFEKCHPWTSCETKDLVVQQAGTNKTDVVCGPQDRLRALVVIPIIFGILFAILLVLVFIKKVAKKPTNKAPHPKQEPQEINFPDDLPGSNTAAPVQETLHGCQPVTQEDGKESRISVQERQ

Open

Disease

Brain cancer, Crohn disease, Diabetes mellitus, Lupus erythematosus, Mature B-cell leukaemia, Melanoma, Motor neuron disease, Multiple sclerosis, Myasthenia gravis, Ovarian cancer, Rheumatoid arthritis, Sjogren syndrome, Solid tumour/cancer, Thrombocytopenia, Thyrotoxicosis, Transplant rejection

Approved Drug

Clinical Trial Drug

18 +

Discontinued Drug

2 +

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Detailed Information

The transmembrane protein receptor CD40 is a member of the tumor necrosis factor (TNF) receptor superfamily, which participates in the costimulation of immune cells. CD40 is expressed by antigen-presenting cells (APCs) including dendritic cells (DCs), macrophages, B-cells, and monocytes but is also expressed on other cell types such as endothelial cells, epithelial cells, and platelets and CD40 expression has been demonstrated on multiple tumor cells, including renal cancer cells and B cell lymphoma. Therefore, therapeutic CD40 ligation could act both through general immune activation and through the opsonization of tumor cells for immune effector mechanisms, an effect that provides an operable target pathway for cancer immunotherapy.

CD40-CD40L Pathway and Human Diseases

The ligand for CD40 is CD40 ligand (i.e. CD154) that is expressed on a variety of cell types, including activated B cells, activated CD4 T cells, memory CD8 T cells, endothelial cells, granulocytes, activated natural killer cells, smooth muscle cells, macrophages, and activated platelets. On DCs, CD40 activation leads to two main cellular phenotypes. First, CD40 activation results in the upregulation of major histocompatibility complex (MHC) molecules, increased expression of immunoglobulin (Ig) superfamily costimulatory molecules, and upregulation of other tumor necrosis factor (TNF) superfamily ligands such as CD137 ligand, OX40 ligand, and GITR ligand. Thus, CD40 is described as proximal in the cascade of adaptive immune activation, which receives a signal from CD40L on CD4+ cells, and then upregulates on DCs a set of secondary stimulatory molecules, thus achieving enhanced antigen presentation and activation of CD8+ T cells.

It is known that CD40 ligation induces expression of intercellular adhesion molecule (ICAM-1) and Fas/Fas ligand on CD40+ tumor cells and may stimulate the secretion of GROa, IL-6, IL-8, TNF-α, and GM-CSF. More specifically, ICAM-1 and Fas expression is heavily induced in renal cancer cells where the gene expression of GM-CSF, IL-23, monocyte chemoattractant protein-1 (MCP-1), interferon gamma-induced protein (IP-10), and ITAC is also upregulated. Thus, ligation of CD40 should lead to the recruitment of immune effector cells with tumoricidal effects into the tumor microenvironment. Moreover, CD40 ligation of carcinoma and melanoma cells has been shown to inhibit entry into the S-phase and thereby the proliferation of the CD40 expressing tumor cells. Combined with the initiation of apoptosis, this may lead to tumor regression and in vitro engagement of CD40 has been shown to inhibit the growth of solid tumor cells and high-grade B cell lymphoma cell lines. In contrast, in other B cell derived malignancies such as CLL and NHL, CD40 ligation has shown to stimulate the tumor cell survival through germinal center (GC) formation. Thus, CD40 is considered to be an attractive target for cancer immunotherapy.

CD40 in Cancer Immunotherapy

These observations have led to efforts to develop CD40 agonists as new immune therapy for patients with cancer. The use of CD40 agonists for inducing anti-tumor immune responses has primarily focused on strategies that ignite T cell-dependent anti-tumor immunity. However, CD40 agonists have also been found to directly induce malignant cell apoptosis and to modulate innate immune surveillance, which has important therapeutic significance. Therefore, three major approaches to the use of CD40 agonists in cancer have emerged: (i) direct anti-tumor activity, (ii) induction of T cell immunity, and (iii) activation of innate immunosurveillance).

CD40 Figure 1. Strategies for applying CD40 agonists in cancer therapy. (Beatty G L, et al., 2017)

In hematological malignancies, CD40 antibodies have been used to induce direct cytotoxic activity and to induce mechanisms of antibody-dependent cellular cytotoxicity and antibody dependent cellular phagocytosis. In contrast, in solid malignancies, the main focus has been to use CD40 agonists to provoke T cell dependent anti-tumor immunity. Preclinical data show that this may be due to a subset of macrophages that regulate the capacity of a CD40 agonist to stimulate tumor-specific T cells and the need for additional immune stimuli (e.g. TLR agonists or cytokines) to effectively prime and boost tumor-specific T cell immunity. By comparison, CD40 agonists have recently been shown to also condition tumors for enhanced sensitivity to chemotherapy. This finding may explain encouraging results of chemotherapy combined with CD40 agonists in patients with pancreatic carcinoma and deserves further clinical studies to determine the potential of this strategy. In conclusion, CD40 remains a promising target for cancer immunotherapy that has shown some activity in patients.

References:

Hassan S B, et al. Anti-CD40-mediated cancer immunotherapy: an update of recent and ongoing clinical trials. Immunopharmacology and immunotoxicology, 2014, 36(2): 96-104.
Beatty G L, et al. Cancer immunotherapy: activating innate and adaptive immunity through CD40 agonists. Expert review of anticancer therapy, 2017, 17(2): 175-186.
Vonderheide R H. CD40 agonist antibodies in cancer immunotherapy. Annual Review of Medicine, 2020, 71: 47-58.
Seijkens T T P, et al. Targeting CD40-induced TRAF6 signaling in macrophages reduces atherosclerosis[J]. Journal of the American College of Cardiology, 2018, 71(5): 527-542.
Karnell J L, et al. Targeting the CD40-CD40L pathway in autoimmune diseases: Humoral immunity and beyond. Advanced drug delivery reviews, 2019, 141: 92-103.

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