Abstract 1704: Concurrent expression of PD-1 and TIGIT increased on effector T cells of CLL patients

Abstract

Abstract Tumor cells avoid elimination by the host immune system using physiological immune checkpoint pathways. Among various lymphoma subtypes, most non-Hodgkin lymphoma subtypes express multiple immune checkpoint molecules simultaneously and have a lower sensitivity to PD1/PD-L1 blockade. TIGIT is a co-inhibitory molecule primarily expressed on NK cells, regulatory CD4+ T cells, and cytotoxic CD8+ T cells and inhibits T cell activation and reduces target cell killing by NK cells. Chronic lymphocytic leukemia (CLL) is a B-cell neoplasm, and pathogenesis involves T-cell exhaustion mediated by an upregulation of various checkpoint molecules. However, there has been no solid evidence on the effects of using immune checkpoint inhibitors in CLL patients until now. Therefore, we designed translational research with a hypothesis that the PD-1/PD-L1 and TIGIT/CD155 pairs are pathways to induce T-cell exhaustion in CLL patients.We used the bone marrow mononuclear cells (BMMC) of 14 CLL patients and seven controls (normal bone marrow findings). All data were acquired via multi-color flow cytometry using an Fc receptor (FcR) blocking reagent, LIVE/DEAD™ Fixable viability dye and fluorochrome-conjugated antibodies for cell surface antigens.We confirmed the frequencies of total NK (CD3-/CD56+) and NKT-like (CD3+/CD56+) cells were significantly higher in the bone marrow of CLL patients than in the control group. An analysis of co-inhibitory molecules on T cells demonstrated that the expression of PD-1 and TIGIT on total CD4 T, Foxp3-CD4 T and CD8 T cells was significantly higher in the CLL patient group. The concurrent expression of PD-1/TIGIT increased significantly on total CD4 T, Foxp3-CD4 T, and CD8 T cells and a higher co-expression of TIGIT/CD226 on total NK, total CD4 T, and CD8 T cells and increased triple expression of PD-1/TIGIT/CD226 on total CD4 T and Foxp3-CD4 T cells of CLL patients. In addition, TIGIT expression was elevated in all subsets of NKT-like cells (total CD4 NKT-like, Foxp3+CD4 NKT-like Foxp3-CD4 NKT-like and CD8 NKT-like cells) from CLL patients, and PD-1 and CD226 were increased in CD8 NKT-like cells. The co-expression of PD-1/TIGIT and TIGIT/CD226 was significantly elevated on all subsets of NKT-like cells from CLL patients and co-expression of PD-1/CD226 was increased only in the CD8 NKT-like subset. The triple expression of PD-1/TIGIT/CD226 increased significantly on Foxp3+CD4 NKT-like, Foxp3-CD4 NKT-like, and CD8 NKT-like cells from CLL patients than from the control group. Also, regulatory T cells (CD3+/CD56-/CD4+/Foxp3+) from CLL patients expressed significantly higher ligand molecules Galectin-9, PD-L1 and VISTA compared to the control group and leukemic B cells (CD3-CD19+) upregulated Galectin-9.These results support our hypothesis that PD-1 and TIGIT are critical for CLL cells to avoid T cell activation and suggest a dual blockade of PD-1/TIGIT is a promising therapeutic strategy for CLL patients. Citation Format: Jihyun Park, Junshik Hong, Youngil Koh, Byung-Su Kim, Sung-Soo Yoon. Concurrent expression of PD-1 and TIGIT increased on effector T cells of CLL patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1704.