The breakthrough in cancer immunotherapy of targeting PD-1 or PD-L1 and enabling T cells to attack tumor has opened new window for cancer treatment of many tumor types. Many of these immunotherapeutic approaches involve targeting specific immune checkpoints. To better understand the role of checkpoint receptors in cancer immunotherapy and explore new treatments, we analyzed cancer patient PBMCs and dissociated tumor samples from non-small cell lung cancer (NSCLC).
Transcripts of Cancer Testis (CT) antigens (NY-ESO-1, MAGE-A1, and MAGE-A3), a novel T cell inhibitory checkpoint receptor (TIGIT), and its respective ligands (PVR and PVRL2) as well as PDL1 from a cohort of NSCLC patients was analyzed. Immune cells from these patient samples were profiled and NYESO1/HLAA2 tetramer was used to detect NYESO1 specific CD8 T cells in HLAA2+ patients. Intracellular cytokine secretion was analyzed using a specially designed multiparameter flow cytometry panel for both general and NYESO-1+ CD8 T cells.
The correlation between CT antigens, immune checkpoints, and effector T cell signature (CD8A, IFN-gamma, and Granzyme A) may help us understand 1) why certain patients have inflamed tumors and others have “cold” tumors; 2) why certain patients respond to anti-PD(L)1 therapy and others do not respond. Antibodies targeting both PD1 and another novel immune checkpoint receptor TIGIT showed best stimulatory effect on both antigen specific CD8 T cell number and intracellular IFN-gamma staining of those cells.
The data suggest that immune checkpoint receptor antibodies can be screened in real patient immune cells. Cotargeting multiple immune checkpoint receptors may provide superior efficacy to targeting single immune checkpoint receptor.
Clinical trial identification
Legal entity responsible for the study
Eli Lilly and Company
All authors have declared no conflicts of interest.