Lactate influx promotes immunoevasion in pancreatic cancer by activating autophagy of pancreatic stellate cells
It has been reported that lactate plays as a bridging signaling molecule to coordinates tumor cell and tumor stroma. As pancreatic stellate cells (PSC) is the most majority and functional cells in tumor microenvironment (TME) of pancreatic cancer (PC), whether the lactate involving the crosstalk between PSC and pancreatic acinar cells (PACs) in tumorigenesis of PC has not been defined. The present study showed that lactate transporter, monocarboxylate transporter 1 (MCT1) was predominantly expressed in pancreatic stellate cells (PSC), and correlates with worse prognosis in PC patients. Moreover, we revealed lactate induced autophagy-mediated activation of PSC, while knockout MCT1 in PSC  (PSC-MCT1-/- mice) obviously inhibited the proliferation and metastasis of  PC in vivo. Meanwhile, results of single-cell sequence demonstrated that the PD-1 expression in CD8+T cells was dramatically increased. Mechanistically, the MCT1-mediated influx of lactate activated PSC by inducing lactylation of lysine residues K356 and K781 on Vps34, a key regulator for autophagy. Moreover, the PSC-derived CXCL9/CXCL10 upregulated PD-1 expression via activating CXCR3/STAT3 pathway in CD8+ T. Consistently, the growth of pancreatic tumor in situ was significantly inhibited in mice treated with MCT1 inhibitor AZD3965, which was further suppressed by combination with PD-1 antibody. In conclusion, our study implicates lactate functions as TME transducer mediating activation of PSC and formation of immunosuppressive TME, and indicates the synergistic effect of targeting PSC activation in immune checkpoint therapy in PC. Overall design: Tumors formed by orthotopic pancreatic injection of KPC cells in FLOX/MCT1-/- mice were harvested and prepared for single-cell homogenization. Subsequently, the samples were analyzed using high-throughput expression profiling systems.