NPC1L1 on Pancreatic Adenocarcinoma Cell Functions as A Two-pronged Checkpoint against Antitumor Activity

Pancreatic adenocarcinoma (PAAD) is a highly lethal malignancy with an immunosuppressive microenvironment and a limited immunotherapy response1-5. Cholesterol is necessary for rapid growth of cancer cells, and cholesterol metabolism reprogramming is a hallmark of PAAD6. How PAAD cells initiate cholesterol reprogramming to sustain their growth demand and suppressive immunomicroenvironment remains elusive. In this study, we for the first time revealed that PAAD cells overcome cholesterol shortage and immune surveillance via ectopically overexpressing NPC1L1, a cholesterol transporter7, but functions as a two-pronged checkpoint which not only directly suppressing TCR activation of CD8+T cells but also hijacking the intracellular cholesterol from CD8+T cells. In vivo, we showed that ezetimibe, an NPC1L1 inhibitor usually for hypercholesterolemia, efficiently prevented PAAD cells from depriving cholesterol of CD8+T cells, and improved the antitumor immunity of PAAD to synergize with PD-1 blockade, suggesting NPC1L1 as a promising target to rescue the antitumor activity in PAAD.