CD40

Overview

CD40 is a tumor necrosis factor (TNF) receptor superfamily member expressed on antigen-presenting cells (APCs), including dendritic cells (DC), B cells, macrophages, and monocytes and plays a key role in the activation of the immune system.1,2 Expression extends to a variety of nonhematopoietic cell types, including neuronal, epithelial, and endothelial cells and fibroblasts.1,2


CD40 ligand (CD40L; also known as CD154) is primarily expressed on activated CD4+ helper T cells.1-3

CD40/CD40L interactions promote both innate and adaptive immune responses. The effect is dependent on both the type of cell expressing CD40 and the microenvironment in which the interaction occurs.1-5

  • CD40 engagement on DCs promotes cytokine production, induces the expression of costimulatory molecules on their surface, and facilitates the cross-presentation of antigens, thus promoting their maturation into fully competent APCs.2
  • CD40 engagement on immature and mature B cells activates proliferation, differentiation, and immunoglobulin (Ig) production.1,2
  • The CD40/CD40L axis bridges signaling between the innate and the adaptive immune system as it was shown to activate natural killer cells.6
  • CD40 engagement on activated myeloid cells, such as macrophages and monocytes, increases the level of activation and induces tumoricidal substances, such as reactive oxygen species and nitric oxide.1,2

IMPLICATIONS IN CANCER

CD40 agonism has the potential to generate anticancer immunity by various mechanisms through initiating antigen presentation, promoting adaptive immunity, and reprograming suppressive tumor microenvironment.1

  • Activate DCs and increase their ability to process and present tumor-associated antigens to T lymphocytes.1
  • Reprogram tumor-associated macrophages towards an antitumor M1 phenotype (classically activated macrophages that show enhanced ability to phagocytose).6,7

Compared with cancer tissue, normal tissues exhibited very low to no CD40 levels, underscoring the potential of CD40 as a cancer-specific immunological target.6

Oncogenic Expression6

Substantial CD40 expression was detected in a variety of frequent solid cancer types including:

  • Breast Cancer
    • Substantial CD40 expression was detected in 53% of breast cancer samples.
  • Lung Cancer
    • Substantial CD40 expression was detected in 52% (67/129) of lung cancer samples.
  1. Vonderheide RH, Glennie MJ. Agonistic CD40 antibodies and cancer therapy. Clin Cancer Res. 2013;19(5):1035-1043.
  2. van Kooten C, Banchereau J. CD40-CD40 ligand. J Leukoc Biol. 2000;67(1):2-17.
  3. Armitage RJ, Fanslow WC, Strockbine L, et al. Molecular and biological characterization of a murine ligand for CD40. Nature. 1992;357:80-82.
  4. Eliopoulos AG, Young LS. The role of the CD40 pathway in the pathogenesis and treatment of cancer. Curr Opin Pharmacol. 2004;4(4):360-367.
  5. Kawabe T, Matsushima M, Hashimoto N, Imaizumi K, Hasegawa Y. CD40/CD40 ligand interactions in immune responses and pulmonary immunity. Nagoya J Med Sci. 2011;73(3-4):69-78.
  6. Piechutta M, Berghoff AS. New emerging targets in cancer immunotherapy: the role of Cluster of Differentiation 40 (CD40/TNFR5). ESMO Open 2019;4:e000510. doi:10.1136/esmoopen-2019-000510.
  7. Genard G, Lucas S, Michiels C. Reprogramming of Tumor-Associated Macrophages with Anticancer Therapies: Radiotherapy versus Chemo- and Immunotherapies. Front Immunol. 2017;8:828.
  8. Buhtoiarov IN, Sondel PM, Wigginton JM, et al. Anti-tumour synergy of cytotoxic chemotherapy and anti-CD40 plus CpG-ODN immunotherapy through repolarization of tumour-associated macrophages. Immunology. 2011;132(2):226-239.

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