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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