PMID- 33086073 OWN - NLM STAT- MEDLINE DCOM- 20211018 LR - 20211018 IS - 2211-1247 (Electronic) VI - 33 IP - 3 DP - 2020 Oct 20 TI - PPARalpha Inhibition Overcomes Tumor-Derived Exosomal Lipid-Induced Dendritic Cell Dysfunction. PG - 108278 LID - S2211-1247(20)31267-5 [pii] LID - 10.1016/j.celrep.2020.108278 [doi] AB - Dendritic cells (DCs) orchestrate the initiation, programming, and regulation of anti-tumor immune responses. Emerging evidence indicates that the tumor microenvironment (TME) induces immune dysfunctional tumor-infiltrating DCs (TIDCs), characterized with both increased intracellular lipid content and mitochondrial respiration. The underlying mechanism, however, remains largely unclear. Here, we report that fatty acid-carrying tumor-derived exosomes (TDEs) induce immune dysfunctional DCs to promote immune evasion. Mechanistically, peroxisome proliferator activated receptor (PPAR) alpha responds to the fatty acids delivered by TDEs, resulting in excess lipid droplet biogenesis and enhanced fatty acid oxidation (FAO), culminating in a metabolic shift toward mitochondrial oxidative phosphorylation, which drives DC immune dysfunction. Genetic depletion or pharmacologic inhibition of PPARalpha effectively attenuates TDE-induced DC-based immune dysfunction and enhances the efficacy of immunotherapy. This work uncovers a role for TDE-mediated immune modulation in DCs and reveals that PPARalpha lies at the center of metabolic-immune regulation of DCs, suggesting a potential immunotherapeutic target. CI - Copyright (c) 2020 The Authors. Published by Elsevier Inc. All rights reserved. FAU - Yin, Xiaozhe AU - Yin X AD - Protein and Peptide Pharmaceutical Laboratory, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100864, China. FAU - Zeng, Wenfeng AU - Zeng W AD - Protein and Peptide Pharmaceutical Laboratory, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100864, China. Electronic address: zengwenfeng@ibp.ac.cn. FAU - Wu, Bowen AU - Wu B AD - Protein and Peptide Pharmaceutical Laboratory, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100864, China; Laboratory of Proteomics, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China. FAU - Wang, Luoyang AU - Wang L AD - Department of Chemical Engineering, Tsinghua University, Beijing 100084, China. FAU - Wang, Zihao AU - Wang Z AD - Protein and Peptide Pharmaceutical Laboratory, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100864, China. FAU - Tian, Hongjian AU - Tian H AD - Protein and Peptide Pharmaceutical Laboratory, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100864, China. FAU - Wang, Luyao AU - Wang L AD - Protein and Peptide Pharmaceutical Laboratory, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100864, China. FAU - Jiang, Yunhan AU - Jiang Y AD - Department of Anatomy and Cell Biology, College of Medicine, University of Florida, Gainesville, FL 32610-3033, USA. FAU - Clay, Ryan AU - Clay R AD - Department of Anatomy and Cell Biology, College of Medicine, University of Florida, Gainesville, FL 32610-3033, USA. FAU - Wei, Xiuli AU - Wei X AD - Protein and Peptide Pharmaceutical Laboratory, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China. FAU - Qin, Yan AU - Qin Y AD - Protein and Peptide Pharmaceutical Laboratory, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China. FAU - Zhang, Fayun AU - Zhang F AD - Protein and Peptide Pharmaceutical Laboratory, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China. FAU - Zhang, Chunling AU - Zhang C AD - Protein and Peptide Pharmaceutical Laboratory, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China. FAU - Jin, Lingtao AU - Jin L AD - Department of Anatomy and Cell Biology, College of Medicine, University of Florida, Gainesville, FL 32610-3033, USA. Electronic address: ljin1@ufl.edu. FAU - Liang, Wei AU - Liang W AD - Protein and Peptide Pharmaceutical Laboratory, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100864, China. Electronic address: weixx@sun5.ibp.ac.cn. LA - eng GR - R37 CA249305/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. PL - United States TA - Cell Rep JT - Cell reports JID - 101573691 RN - 0 (Fatty Acids) RN - 0 (Lipids) RN - 0 (PPAR alpha) RN - 0 (PPARA protein, human) SB - IM MH - Animals MH - Cell Line MH - Cells, Cultured MH - Dendritic Cells/immunology/*physiology MH - Fatty Acids/metabolism MH - Female MH - Humans MH - Lipid Metabolism MH - Lipids MH - Liver/metabolism MH - Male MH - Mice MH - Mice, Inbred BALB C MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Mitochondria/metabolism MH - Oxidation-Reduction MH - Oxidative Phosphorylation MH - PPAR alpha/*metabolism/physiology PMC - PMC7771208 MID - NIHMS1639624 OTO - NOTNLM OT - DC OT - PPARalpha OT - dendritic cell OT - immune dysfunction OT - lipid metabolism OT - tumor-derived exosome COIS- Declaration of Interests The authors declare no competing interests. EDAT- 2020/10/22 06:00 MHDA- 2021/10/21 06:00 PMCR- 2020/12/29 CRDT- 2020/10/21 20:06 PHST- 2019/09/25 00:00 [received] PHST- 2020/06/14 00:00 [revised] PHST- 2020/09/23 00:00 [accepted] PHST- 2020/10/21 20:06 [entrez] PHST- 2020/10/22 06:00 [pubmed] PHST- 2021/10/21 06:00 [medline] PHST- 2020/12/29 00:00 [pmc-release] AID - S2211-1247(20)31267-5 [pii] AID - 10.1016/j.celrep.2020.108278 [doi] PST - ppublish SO - Cell Rep. 2020 Oct 20;33(3):108278. doi: 10.1016/j.celrep.2020.108278.