Helmholtz Center Munich, Germany: 1Immunoanalytics Research Group - Tissue control of Immunocytes; 2Institute of Structural Biology
Activation of costimulatory pathways in cytotoxic T lymphocytes expressing chimeric antigen receptors (CARs) can boost effector activity, tumor rejection and long-term T cell persistence. When using T cell receptors (TCR) instead of CARs, the lack of co-stimulatory signals hampers robust anti-tumoral response hence limiting clinical efficacy. Our project aims at generating chimeric co-stimulatory proteins (CCP) consisting of intracellular co-stimulatory domains (ICD) fused to extracellular protein domains (ECD) for which ligands are expressed in solid tumors.
PD-L1 and CD40L ECDs were selected to combine them in different formats with the ICDs of CD28 and 4-1BB. With this approach it is expected to strengthen the TCR signaling, while the PD-1 ECD is predicted to counteract T cell inhibition caused by native PD-1/PD-L1 interaction, and CD40L ECD could potentially lead to activation of tumor resident antigen presenting cells, targeting tumor endothelium and TCR-MHC independent apoptotic effect on tumor cells.
The CCPs were expressed in human T cells along with antigen-specific TCRs of different functional avidity. Facilitated co-stimulation on T cell effector function was tested in in vitro assays and in mouse tumor models.
The structural design of the CCPs strongly influenced intensity and dynamics of surface expression, which could be regulated through antigen stimulation. Ligation of the CCP in the context of TCR-stimulation modulated intracellular signaling cascades and enhanced TCR-induced cytokine secretion and cytotoxicity. T cells with a TCR of low functional avidity achieved effector activity comparable to T cells with a high avidity TCR. Adoptive transfer in mice carrying large established tumors demonstrated reversal of Th2 polarization and stronger proliferation of engineered T cells. Thus, chimeric co-stimulatory receptors constitute promising tools to be included in the engineering process of T cells to endow them with features for improved performance in the tumor milieu.
Credits: None available.
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