Novel Strategy to Regulate PD-L1 Expression and Enhance Anti-Tumor Effect

Abstract

Abstract The programmed death 1/PD ligand 1(PD-1/PD-L1 axis is a major player in the tumor immune evasion strategy. We show that the immunomodulatory small tellurium molecules, AS101 [ammonium trichloro(dioxoethylene-o, o′)tellurate] and SAS [octa-O-bis-(R,R)-tartarate ditellurane], suppress PD-L1 expression on a variety of human and mouse malignant cells by inhibition of the α4β1 VLA-4 (very late antigen-4) integrin activity. As a consequence, pAkt and its downstream effector pNFκB are inhibited. VLA-4/pAkt/pNFκB signaling blockade was found crucial for decreasing PD-L1 expression. Moreover, the tellurium compounds had physiological effects. SAS augmented killing of human and mouse malignant cells by stimulated syngeneic splenocytes or CD8+ T cells. Furthermore, SAS prevented the development of chemoresistance in malignant cells. IL-10 production by tumor cells, the inhibition of which by AS101 we showed suppressed chemoresistance, is shown here to be closely associated with inhibition of VLA-4 and PD-L1 expression suggesting that AS101 and SAS compounds may, at least partially, induce chemosensitivity by virtue of inhibition of the VLA-4/IL-10/PD-L1 pathway. AS101 or SAS treatment of B16 melanoma-bearing mice decreased tumor cell PD-L1 expression, led to increased CD8+ T-cell infiltration into the tumors and tumor shrinkage. Combined treatment with αPD-1 antibody and either of the tellurium compounds significantly increased antitumor effects. These results collectively suggest that VLA-4 integrin signaling serves as a critical component of cancer evasion and is a potential target for cancer treatment. Furthermore, AS101 or SAS may be suitable for effective combinatorial cancer immunotherapy with αPD-1.