Regulation of ROS in myeloid-derived suppressor cells through targeting fatty acid transport protein 2 enhanced anti-PD-L1 tumor immunotherapy.
Despite the remarkable success and efficacy of immune checkpoint blockade (ICB) therapy against the PD-1/PD-L1 axis, it induces sustained responses in a sizeable minority of cancer patients due to the activation of immunosuppressive factors such as myeloid-derived suppressor cells (MDSCs). Inhibiting the immunosuppressive function of MDSCs is critical for successful cancer ICB therapy. Interestingly, lipid metabolism is a crucial factor in modulating MDSCs function. Fatty acid transport protein 2 (FATP2) conferred the function of PMN-MDSCs in cancer via the upregulation of arachidonic acid metabolism. However, whether regulating lipid accumulation in MDSCs by targeting FATP2 could block MDSCs reactive oxygen species (ROS) production and enhance PD-L1 blockade-mediated tumor immunotherapy remains unexplored. Here we report that FATP2 regulated lipid accumulation, ROS, and immunosuppressive function of MDSCs in tumor-bearing mice. Tumor cells-derived granulocyte macrophage-colony stimulating factor (GM-CSF) induced FATP2 expression in MDSCs by activation of STAT3 signaling pathway. Pharmaceutical blockade of FATP2 expression in MDSCs by lipofermata decreased lipid accumulation, reduced ROS, blocked immunosuppressive activity, and consequently inhibited tumor growth. More importantly, lipofermata inhibition of FATP2 in MDSCs enhanced anti-PD-L1 tumor immunotherapy via the upregulation of CD107a and reduced PD-L1 expression on tumor-infiltrating CD8+T-cells. Furthermore, the combination therapy blocked MDSC's suppressive role on T- cells thereby enhanced T-cell's ability for the production of IFN-γ. These findings indicate that FATP2 plays a key role in modulating lipid accumulation-induced ROS in MDSCs and targeting FATP2 in MDSCs provides a novel therapeutic approach to enhance anti-PD-L1 cancer immunotherapy.
['Adeshakin|Adeleye Oluwatosin|AO|', 'Liu|Wan|W|', 'Adeshakin|Funmilayo O|FO|', 'Afolabi|Lukman O|LO|', 'Zhang|Mengqi|M|', 'Zhang|Guizhong|G|', 'Wang|Lulu|L|', 'Li|Zhihuan|Z|', 'Lin|Lilong|L|', 'Cao|Qin|Q|', 'Yan|Dehong|D|', 'Wan|Xiaochun|X|']
D000818:Animals D060890:B7-H1 Antigen D045744:Cell Line, Tumor D002681:China D003066:Coenzyme A Ligases D050612:Fatty Acid Transport Proteins D016178:Granulocyte-Macrophage Colony-Stimulating Factor D006801:Humans D000082082:Immune Checkpoint Inhibitors D007167:Immunotherapy D050356:Lipid Metabolism D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D000072737:Myeloid-Derived Suppressor Cells D017382:Reactive Oxygen Species D050796:STAT3 Transcription Factor D015398:Signal Transduction D013141:Spiro Compounds D013601:T-Lymphocytes D013830:Thiadiazoles
ROS Anti-PD-L1 tumor immunotherapy MDSCs Lipid metabolism FATP2