Mechanistic basis of co-stimulatory CD40-CD40L ligation mediated regulation of immune responses in cancer and autoimmune disorders

• Published in: Immunobiology (1979) 2020-03, Vol.225 (2), p.151899-151899, Article 151899
• Main Authors: Chand Dakal, Tikam, Dhabhai, Bhanupriya, Agarwal, Disha, Gupta, Ritisha, Nagda, Girima, Meena, Asha Ram, Dhakar, Ramgopal, Menon, Athira, Mathur, Riya, Mona, Yadav, Vinod, Sharma, Amit
• Format: Article
• Language: English
• Subjects: Autoimmune disorders; Cancer; CD154/CD40L; CD40; CD40/CD40L ligation; Co-stimulatory signal
• ISSN: 0171-2985; 1878-3279
• DOI: 10.1016/j.imbio.2019.151899

Generation of an accurate humoral and a cell mediated adaptive immune responsesare dictated by binding of an antigen to a T- and a B-cell receptor, respectively (first signal) followed by ligation of costimulatory molecules (second signal). CD40, a costimulatory receptor molecule, expressed mainly on antigen presenting cells, some non-immune cells and tumors, binds to CD40 ligand molecule expressed transiently on T-cells and non-immune cells under inflammatory conditions. In the past decade, the CD40-CD40L interaction has emerged as an immune-potentiating system that governs and regulates host immune response against various diseases and pathogens, failing of which results in detrimental patho-physiologies including cancer and autoimmune disorders. CD40-CD40L transduces immune signals intracellularly via TRAF-dependent and independent mechanisms and further downstream by different MAPK pathways and transcription factors such as NF-κB, p38 etc. While CD40 signaling pathway through its cognate interaction between B and T cells promotes activation and proliferation of B-cells, Ig class switching, and generation of B cell memory; however, CD40-CD40L interaction involving other APCs and non-immune cells relay distinct cell signaling resulting in production of a variety of cytokines/chemokines and cell adhesion molecules ultimately conferring host defense against pathogen. In cancer and autoimmune disorders, CD40-CD40L interaction is also responsible for aberrant expression of many disease specific markers, class I/II MHC molecules and other co-stimulatory molecules such as B7 and CD28 in cell- and disease-specific manner. In the present review, the current state of understanding about the CD40-CD40L mediated regulation of immune and non-immune cells is presented. The current paradigm is to target CD40 using agonist anti-CD40 mAbs alone or in synergistic combination with chemotherapy in order to harness or confer anti-tumor and anti-inflammatory immunity.