PPARα Inhibition Overcomes Tumor-Derived Exosomal Lipid-Induced Dendritic Cell Dysfunction

Abstract

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) α 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 PPARα 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 PPARα lies at the center of metabolic-immune regulation of DCs, suggesting a potential immunotherapeutic target.

References 49

1. 1.

   Apetoh L, Locher C, Ghiringhelli F, Kroemer G, and Zitvogel L (2011 ). Harnessing dendritic cells in cancer. Semin. Immunol 23, 42–49.

   Not in our library10.1016/j.smim.2011.01.003

2. 2.

   Cabodevilla AG, Sánchez-Caballero L, Nintou E, Boiadjieva VG, Pica-toste F, Gubern A, and Claro E (2013 ). Cell survival during complete nutrient deprivation depends on lipid droplet-fueled β-oxidation of fatty acids. J. Biol. Chem 288, 27777–27788.

   Not in our library10.1074/jbc.m113.466656

3. 3.

   Calder PC (2010 ). Lipid-laden dendritic cells fail to function. Cell Res. 20, 1089–1091.

   Not in our library10.1038/cr.2010.124

4. 4.

   Cubillos-Ruiz JR, Silberman PC, Rutkowski MR, Chopra S, Perales-Puchalt A, Song M, Zhang S, Bettigole SE, Gupta D, Holcomb K, (2015 ). ER Stress Sensor XBP1 Controls Anti-tumor Immunity by Disrupting Dendritic Cell Homeostasis. Cell 161, 1527–1538.

   Not in our library10.1016/j.cell.2015.05.025

5. 5.

   Dáňová K, Klapetková A, Kayserová J, Šedivá A, Špíšek R, and Jelín-ková LP (2015 ). NF-κB, p38 MAPK, ERK1/2, mTOR, STAT3 and increased glycolysis regulate stability of paricalcitol/dexamethasone-generated tolerogenic dendritic cells in the inflammatory environment. Oncotarget 6, 14123–14138.

   Not in our library10.18632/oncotarget.4234

6. 6.

   DeVito NC, Plebanek MP, Theivanthiran B, and Hanks BA (2019 ). Role of Tumor-Mediated Dendritic Cell Tolerization in Immune Evasion. Front. Immunol 10, 2876.

   Not in our library10.3389/fimmu.2019.02876

7. 7.

   Diamond MS, Kinder M, Matsushita H, Mashayekhi M, Dunn GP, Arch-ambault JM, Lee H, Arthur CD, White JM, Kalinke U, (2011 ). Type I interferon is selectively required by dendritic cells for immune rejection of tumors. J. Exp. Med 208, 1989–2003.

   Not in our library10.1084/jem.20101158

8. 8.

   Dong H, and Bullock TN (2014 ). Metabolic influences that regulate dendritic cell function in tumors. Front. Immunol 5, 24.

   Not in our library10.3389/fimmu.2014.00024

9. 9.

   Everts B, and Pearce EJ (2014 ). Metabolic control of dendritic cell activation and function: recent advances and clinical implications. Front. Immunol 5, 203.

   Not in our library10.3389/fimmu.2014.00203

10. 10.

    Ferreira GB, Vanherwegen AS, Eelen G, Gutiérrez ACF, Van Lommel L, Marchal K, Verlinden L, Verstuyf A, Nogueira T, Georgiadou M, (2015 ). Vitamin D3 Induces Tolerance in Human Dendritic Cells by Activation of Intracellular Metabolic Pathways. Cell Rep. 10, 711–725.

    Not in our library10.1016/j.celrep.2015.01.013

11. 11.

    Fonseca P, Vardaki I, Occhionero A, and Panaretakis T (2016 ). Metabolic and Signaling Functions of Cancer Cell-Derived Extracellular Vesicles. Int. Rev. Cell Mol. Biol 326, 175–199.

    Not in our library10.1016/bs.ircmb.2016.04.004

12. 12.

    Gardner A, and Ruffell B (2016 ). Dendritic Cells and Cancer Immunity. Trends Immunol. 37, 855–865.

    Not in our library10.1016/j.it.2016.09.006

13. 13.

    Garris CS, Arlauckas SP, Kohler RH, Trefny MP, Garren S, Piot C, Engblom C, Pfirschke C, Siwicki M, Gungabeesoon J, (2018 ). Successful Anti-PD-1 Cancer Immunotherapy Requires T Cell-Dendritic Cell Crosstalk Involving the Cytokines IFN-gamma and IL-12. Immunity 49, 1148–1161.e7.

    Not in our library10.1016/j.immuni.2018.09.024

14. 14.

    Grevengoed TJ, Martin SA, Katunga L, Cooper DE, Anderson EJ, Murphy RC, and Coleman RA (2015 ). Acyl-CoA synthetase 1 deficiency alters cardiolipin species and impairs mitochondrial function. J. Lipid Res 56, 1572–1582.

    Not in our library10.1194/jlr.m059717

15. 15.

    Haraszti RA, Didiot MC, Sapp E, Leszyk J, Shaffer SA, Rockwell HE, Gao F, Narain NR, DiFiglia M, Kiebish MA, (2016 ). High-resolution proteomic and lipidomic analysis of exosomes and microvesicles from different cell sources. J. Extracell. Vesicles 5, 32570.

    Not in our library10.3402/jev.v5.32570

16. 16.

    Herber DL, Cao W, Nefedova Y, Novitskiy SV, Nagaraj S, Tyurin VA, Corzo A, Cho HI, Celis E, Lennox B, (2010 ). Lipid accumulation and dendritic cell dysfunction in cancer. Nat. Med 16, 880–886.

    Not in our library10.1038/nm.2172

17. 17.

    Holtzhausen A, Zhao F, Evans KS, Tsutsui M, Orabona C, Tyler DS, and Hanks BA (2015 ). Melanoma-Derived Wnt5a Promotes Local Dendritic-Cell Expression of IDO and Immunotolerance: Opportunities for Pharmacologic Enhancement of Immunotherapy. Cancer Immunol. Res 3, 1082–1095.

    Not in our library10.1158/2326-6066.cir-14-0167

18. 18.

    Jakobsen MA, Petersen RK, Kristiansen K, Lange M, and Lillevang ST (2006 ). Peroxisome proliferator-activated receptor alpha, delta, gamma1 and gamma2 expressions are present in human monocyte-derived dendritic cells and modulate dendritic cell maturation by addition of subtype-specific ligands. Scand. J. Immunol 63, 330–337.

    Not in our library10.1111/j.1365-3083.2006.01745.x

19. 19.

    Kelly DP, and Scarpulla RC (2004 ). Transcriptional regulatory circuits controlling mitochondrial biogenesis and function. Genes Dev. 18, 357–368.

    Not in our library10.1101/gad.1177604

20. 20.

    König B, Rauer C, Rosenbaum S, Brandsch C, Eder K, and Stangl GI (2009 ). Fasting Upregulates PPARalpha Target Genes in Brain and Influences Pituitary Hormone Expression in a PPARalpha Dependent Manner. PPAR Res. 2009, 801609.

    Not in our library10.1155/2009/801609

21. 21.

    Lam SM, Wang R, Miao H, Li B, and Shui G (2018 ). An integrated method for direct interrogation of sphingolipid homeostasis in the heart and brain tissues of mice through postnatal development up to reproductive senescence. Anal. Chim. Acta 1037, 152–158.

    Not in our library10.1016/j.aca.2018.01.015

22. 22.

    Lei J, Hasegawa H, Matsumoto T, and Yasukawa M (2010 ). Peroxisome proliferator-activated receptor α and γ agonists together with TGF-β convert human CD4+CD25- T cells into functional Foxp3+ regulatory T cells. J. Immunol 185, 7186–7198.

    Not in our library10.4049/jimmunol.1001437

23. 23.

    Liu Z, Zhou C, Qin Y, Wang Z, Wang L, Wei X, Zhou Y, Li Q, Zhou H, Wang W, (2017 ). Coordinating antigen cytosolic delivery and danger signaling to program potent cross-priming by micelle-based nanovaccine. Cell Discov. 3, 17007.

    Not in our library10.1038/celldisc.2017.7

24. 24.

    Loftus RM, and Finlay DK (2016 ). Immunometabolism: Cellular Metabolism Turns Immune Regulator. J. Biol. Chem 291, 1–10.

    Not in our library10.1074/jbc.r115.693903

25. 25.

    Lu J, Lam SM, Wan Q, Shi L, Huo Y, Chen L, Tang X, Li B, Wu X, Peng K, (2019 ). High-Coverage Targeted Lipidomics Reveals Novel Serum Lipid Predictors and Lipid Pathway Dysregulation Antecedent to Type 2 Diabetes Onset in Normoglycemic Chinese Adults. Diabetes Care 42, 2117–2126.

    Not in our library10.2337/dc19-0100

26. 26.

    Malinarich F, Duan K, Hamid RA, Bijin A, Lin WX, Poidinger M, Fair-hurst AM, and Connolly JE (2015 ). High mitochondrial respiration and glycolytic capacity represent a metabolic phenotype of human tolerogenic dendritic cells. J. Immunol 194, 5174–5186.

    Not in our library10.4049/jimmunol.1303316

27. 27.

    Milane L, Singh A, Mattheolabakis G, Suresh M, and Amiji MM (2015 ). Exosome mediated communication within the tumor microenvironment. J. Control. Release 219, 278–294.

    Not in our library10.1016/j.jconrel.2015.06.029

28. 28.

    Mulcahy LA, Pink RC, and Carter DR (2014 ). Routes and mechanisms of extracellular vesicle uptake. J. Extracell. Vesicles 3.

    Not in our library10.3402/jev.v3.24641

29. 29.

    Palucka K, and Banchereau J (2013 ). Dendritic-cell-based therapeutic cancer vaccines. Immunity 39, 38–48.

    Not in our library10.1016/j.immuni.2013.07.004

30. 30.

    Preynat-Seauve O, Schuler P, Contassot E, Beermann F, Huard B, and French LE (2006 ). Tumor-infiltrating dendritic cells are potent antigen-presenting cells able to activate T cells and mediate tumor rejection. J. Immunol 176, 61–67.

    Not in our library10.4049/jimmunol.176.1.61

31. 31.

    Ramakrishnan R, Tyurin VA, Veglia F, Condamine T, Amoscato A, Mohammadyani D, Johnson JJ, Zhang LM, Klein-Seetharaman J, Celis E, (2014 ). Oxidized lipids block antigen cross-presentation by dendritic cells in cancer. J. Immunol 192, 2920–2931.

    Not in our library10.4049/jimmunol.1302801

32. 32.

    Rambold AS, Cohen S, and Lippincott-Schwartz J (2015 ). Fatty acid trafficking in starved cells: regulation by lipid droplet lipolysis, autophagy, and mitochondrial fusion dynamics. Dev. Cell 32, 678–692.

    Not in our library10.1016/j.devcel.2015.01.029

33. 33.

    Rubinow KB, Wall VZ, Nelson J, Mar D, Bomsztyk K, Askari B, Lai MA, Smith KD, Han MS, Vivekanandan-Giri A, (2013 ). Acyl-CoA synthetase 1 is induced by Gram-negative bacteria and lipopolysaccharide and is required for phospholipid turnover in stimulated macrophages. J. Biol. Chem 288, 9957–9970.

    Not in our library10.1074/jbc.m113.458372

34. 34.

    Scarlett UK, Rutkowski MR, Rauwerdink AM, Fields J, Escovar-Fadul X, Baird J, Cubillos-Ruiz JR, Jacobs AC, Gonzalez JL, Weaver J, (2012 ). Ovarian cancer progression is controlled by phenotypic changes in dendritic cells. J. Exp. Med 209, 495–506.

    Not in our library10.1084/jem.20111413

35. 35.

    Sim WJ, Ahl PJ, and Connolly JE (2016 ). Metabolism Is Central to Tolerogenic Dendritic Cell Function. Mediators Inflamm. 2016, 2636701.

    Not in our library10.1155/2016/2636701

36. 36.

    Spranger S, Dai D, Horton B, and Gajewski TF (2017 ). Tumor-Residing Batf3 Dendritic Cells Are Required for Effector T Cell Trafficking and Adoptive T Cell Therapy. Cancer Cell 31, 711–723.e4.

    Not in our library10.1016/j.ccell.2017.04.003

37. 37.

    Suvarna K, Honda K, Muroi M, Kondoh Y, Osada H, and Watanabe N (2019 ). A small-molecule ligand of valosin-containing protein/p97 inhibits cancer cell-accelerated fibroblast migration. J. Biol. Chem 294, 2988–2996.

    Not in our library10.1074/jbc.ra118.004741

38. 38.
    Exosome Uptake Depends on ERK1/2-Heat Shock Protein 27 Signaling and Lipid Raft-mediated Endocytosis Negatively Regulated by Caveolin-1 · 2013

    No notice
39. 39.
    Lipid bodies containing oxidatively truncated lipids block antigen cross-presentation by dendritic cells in cancer · 2017

    No notice
40. 40.

    Wahli W, and Michalik L (2012 ). PPARs at the crossroads of lipid signaling and inflammation. Trends Endocrinol. Metab 23, 351–363.

    Not in our library10.1016/j.tem.2012.05.001

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