Antagonizing PD1-TIGIT pathways in Antigen-specific Human T cell clone-based assays supports dual checkpoint inhibition

Identification: Le Saux, Sabine


Description

 

Antagonizing PD1-TIGIT pathways in Antigen-specific Human T cell clone-based assays supports dual checkpoint inhibition
 
Sabine Le Saux, Sophie Li, Robert Shields, Omar Nourzaie, Fernando Ugarte, Laurence Fayadat-Dilman and René de Waal Malefyt.
Merck & Co., Inc., Kenilworth, NJ, USA
 
T cell activation is initiated by signal 1 through antigen-specific TCR recognition and engagement, but a second co-stimulation signal is needed.  This co-stimulation is provided by the interaction of immune-modulator receptors and ligands expressed on the T cells and APC.  These receptor-ligand interactions can either stimulate or inhibit T cell activation.  Since the ligands are also expressed by tumor cells as a mechanism to evade immune surveillance, they are the main targets for the new therapeutics developed in the oncology field.
The establishment of Ag-specific human T cell clones is essential to test different biologics targeting immune-modulator proteins.  In our laboratory, we developed a library of CD4+ T cell clones isolated from whole blood of healthy donors.  Those T cell clones were selected for their antigen-specific recognition of the HLA-DR positive JY cell line.  Upon JY allo-stimulation, human CD4+ T cell clones proliferate and produce IFNγ in a dose-dependent manner.
To analyze the efficacy of antagonistic TIGIT biologics in combination with PD1 blocking pathway, we generated by lentivirus transduction, different JY cell line clones expressing PD-L1, CD155 or PD-L1/CD155.  All JY clones isolated after infection showed a stable expression of the immune-modulator ligands and they inhibited CD4+ T cell clones activation as compared to the parental JY cells.  This inhibition could be reversed by introduction of checkpoint inhibitors.  Our results showed a higher IFNγ production by CD4+ T cell clones after stimulation with JY-PDL1/CD155 in presence of anti-PD1 mAb.  In the same condition, the combination of anti-PD1 and anti-TIGIT antibodies significantly increased the IFNγ production compared to single agent stimulation.
These results support that to improve responses to immuno-therapy; one strategy is to target multiple immuno-modulator molecules in combination.

 

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