The CD40L-CD28 costimulatory switch protein enables to overcome the immunosuppressive tumor microenvironment (TME), that represents a major challenge in immunotherapy and defines the poor outcome of different immune-therapeutic approaches.
The CD40L/CD40 pathway plays a crucial role in immune regulation and homeostasis. The Cluster of Differentiation 40 ligand (CD40L) is a member of the tumor necrosis factor receptor family (TNFR) and predominantly expressed on activated T cells. On CD4+ T cells it primary drives T cell-mediated activation of dendritic cells (DCs) and monocytes. Expression on CD8+ T cells enables T cell expansion and differentiation through DCs.
CD40 and CD28 Receptor
CD40 is an integral membrane protein belonging to the TNFR family. CD40 is present on B cells and DCs, monocytes and macrophages as well as on non-hematopoietic cells such as epithelial and endothelial cells. Expression of CD40 has been confirmed in a wide variety of solid tumors like pancreatic, melanoma, prostate, and lung cancers, as well as in carcinomas of the nasopharynx, bladder, cervix, and ovary.Under physiological conditions CD40 binds to CD40L and can mediate T cell priming. Given the high prevalence of CD40 on immune cells, CD40 represents a new immune-modulating target for various cancer treatment approaches. The CD28 receptor expressed on T cells plays a major role in many T cell processes providing costimulatory signals required for T cell activation and survival.
The role of CD40L-CD28 costimulatory switch protein in T cell functionality
T cell functionality in the solid TME is disturbed resulting in poor tumor penetration, reduced tumor cell killing and enhanced T cell exhaustion and apoptosis. To overcome the immunosuppression TME, we will combine our highly specific TCRs with a CD40L-CD28 costimulatory switch protein. The extracellular protein domain (ECD) of CD40L was combined with the intracellular co-stimulatory domain (ICD) from CD28. Merging the ECD of CD40L with the ICD from CD28 enables increased TCR signalling, but also simplifies infiltration of T cells into the tumor and improves persistence of T cell response through additional activation of tumor-resident antigen-presenting cells (APCs).
Medigene´s CD40L-CD28 costimulatory switch protein may contribute to an enhancement of cellular immune responses in several ways (Figure 1).
- CD40L expressed on activated T cells and CD40 expressed on DC transmits a signal to the APCs that results in upregulation of costimulatory molecules and further stimulation of optimal T cell responses.
- CD40-expressing tumor cells can be subject to apoptosis by direct interaction with CD40L-CD28-engineered T cells independent of MHC/peptide-specific targeting.
- CD40 is found in the TME of the tumor endothelium, where engagement with CD40L-CD28-engineered T cells enables upregulation of adhesion molecules, thereby improving T cell infiltration into tumors.
Merging our TCRs with CD40L-CD28 costimulatory switch protein increases tumor cell killing through improved TCR-T proliferation and facilitates T cell infiltration into the TME, which represents one of the major obstacles in immunotherapy for different types of solid cancers.
Enhancement of cellular immune response in multiple ways by CD40L-CD28 costimulatory switch protein