Novel strategy to regulate pd-l1 expression on nk cells by using the small immunomodulating tellurium compound sas

Blockade of PD-L1 expression on tumor cells via anti–PD-L1 monoclonal antibody (mAb) has shown great promise for successful cancer treatment by overcoming T-cell exhaustion; Despite the important clinical benefits, this drug is associated with significant immune-related adverse effects (irAEs). Other studies showed that patients with PD-L1^- tumors can respond favorably to anti–PD-L1 mAb therapy by activating PD-L1+ NK cells. Those NK cells, which are PDL1+ induced after contact with tumor cells, present higher levels of PD-L1 and display an activated phenotype and enhanced effector functions compared to PD-L1- NK cells, but simultaneously, they directly inhibited CD8 + T cell proliferation in a PD-L1-dependent manner. Here we show that the organotellurium compound (Octa-O-bis-(R,R)-tartarate ditellurane (SAS)) inhibits PD-L1 expression in cancer stimulated NK cells through two mechanisms: Direct inhibition of VLA-4 on NK cells and inhibition of intracellular IL-18 in monocytes. Finally, we show that PD-L1 inhibition by SAS can restore CD8+ T cells proliferation abolished by malignant PD-L1 induced NK cells. This study can provide alternative potential therapeutic value to cancer patients since many SAS studies showed its significant impact on decreasing irAEs.