PIM2 Kinase Regulates TIGIT Expression and Function in NK Cells from Multiple Myeloma Patients

Abstract

Abstract PIM2 kinase influences plasma cell generation and bone loss in multiple myeloma (MM), which is highly associated with tumor progression and is a potential therapeutic target. Although PIM2 kinase is essential for natural killer (NK) cell homeostasis and development, its role in NK cells function remains unclear.Here,the expression of PIM2 kinase was reanalyzed in NK cells from MM patients and healthy donors using single-cell RNA sequencing (RNA-seq). The effect of PIM2 kinase on NK cell immune checkpoints and function were analyzed in NK cell and MM cell co-culture system. Mechanistically, The regulation of PIM2 kinase on TIGIT expression on NK cell was explored through NCBI, UCSC, JASPAR, GEPIA databases and ETS-1 knockdown in NK-92 cells.For further clinical application,PIM2 kinase inhibitors were screened in 160 natural flavonoids through kinase functional assays (ADP-Glo).Our findings reveal that PIM2 kinase was highly expressed in NK cells from MM patients and PIM2 kinase inhibitor increased NK cell function and downregulated TIGIT expression. Mechanistically, the PIM2 kinase inhibitor down-regulated TIGIT expression by reducing transcription factor ETS-1, which binds directly to the TIGIT promoter. For pre-clinical translational application, we screened two natural flavonoids kaempferol and quercetin dihydrate, which show higher efficacy in inhibiting PIM2 kinase. Subsequent co-culture system results demonstrated that kaempferol and quercetin dihydrate can decrease TIGIT expression and improved the anti-myeloma function in NK cells.All the above results confirm PIM2 kinase regulates TIGIT expression and function in NK cells from MM patients.PIM2 kinase inhibitor play a vital role in MM therapy.