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Lipid droplet accumulation mediates macrophage survival and Treg recruitment via the CCL20/CCR6 axis in human hepatocellular carcinoma

Cellular & Molecular Immunology volume 21, pages 1120–1130 (2024)Cite this article

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Abstract

Metabolic changes play a crucial role in determining the status and function of macrophages, but how lipid reprogramming in macrophages contributes to tumor progression is not yet fully understood. Here, we investigated the phenotype, contribution, and regulatory mechanisms of lipid droplet (LD)-laden macrophages (LLMs) in hepatocellular carcinoma (HCC). Enriched LLMs were found in tumor tissues and were associated with disease progression in HCC patients. The LLMs displayed immunosuppressive phenotypes (with extensive expression of TREM2, PD-L1, CD206, and CD163) and attenuated the antitumor activities of CD8+ T cells. Mechanistically, tumor-induced reshuffling of cellular lipids and TNFα-mediated uptake of tumoral fatty acids contribute to the generation of triglycerides and LDs in macrophages. LDs prolong LLM survival and promote CCL20 secretion, which further recruits CCR6+ Tregs to HCC tissue. Inhibiting LLM formation by targeting DGAT1 and DGAT2, which catalyze the synthesis of triglycerides, significantly reduced Treg recruitment, and delayed tumor growth in a mouse hepatic tumor model. Our results reveal the suppressive phenotypes and mechanisms of LLM enrichment in HCC and suggest the therapeutic potential of targeting LLMs for HCC patients.

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References

  1. Cassetta L, Pollard JW. Targeting macrophages: therapeutic approaches in cancer. Nat Rev Drug Discov. 2018;17:887–904.

    Article  CAS  PubMed  Google Scholar 

  2. Wan S, Kuo N, Kryczek I, Zou W, Welling TH. Myeloid cells in hepatocellular carcinoma. Hepatology. 2015;62:1304–12.

    Article  PubMed  Google Scholar 

  3. Wu C, Lin J, Weng Y, Zeng D-N, Xu J, Luo S, et al. Myeloid signature reveals immune contexture and predicts the prognosis of hepatocellular carcinoma. J Clin Investig. 2020;130:4679–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Prendeville H, Lynch L. Diet, lipids, and antitumor immunity. Cell Mol Immunol. 2022;19:432–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Binnewies M, Roberts EW, Kersten K, Chan V, Fearon DF, Merad M, et al. Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat Med. 2018;24:541–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Mantovani A, Marchesi F, Jaillon S, Garlanda C, Allavena P. Tumor-associated myeloid cells: diversity and therapeutic targeting. Cell Mol Immunol. 2021;18:566–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Bian X, Liu R, Meng Y, Xing D, Xu D, Lu Z. Lipid metabolism and cancer. J Exp Med. 2021;218:e20201606.

    Article  CAS  PubMed  Google Scholar 

  8. Goossens P, Rodriguez-Vita J, Etzerodt A, Masse M, Rastoin O, Gouirand V, et al. Membrane cholesterol efflux drives tumor-associated macrophage reprogramming and tumor progression. Cell Metab. 2019;29:1376–89.e4.

    Article  CAS  PubMed  Google Scholar 

  9. Van Den Bossche J, O’Neill LA, Menon D. Macrophage immunometabolism: where are we (Going)? Trends Immunol. 2017;38:395–406.

    Article  PubMed  Google Scholar 

  10. Rabold K, Aschenbrenner A, Thiele C, Boahen CK, Schiltmans A, Smit JWA, et al. Enhanced lipid biosynthesis in human tumor-induced macrophages contributes to their protumoral characteristics. J Immunother Cancer. 2020;8:e000638.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Olzmann JA, Carvalho P. Dynamics and functions of lipid droplets. Nat Rev Mol Cell Biol. 2019;20:137–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Lee-Rueckert M, Lappalainen J, Kovanen PT, Escola-Gil JC. Lipid-laden macrophages and inflammation in atherosclerosis and cancer: an integrative view. Front Cardiovasc Med. 2022;9:777822.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Krahmer N, Farese RV, Walther TC. Balancing the fat: lipid droplets and human disease. EMBO Mol Med. 2013;5:973–83.

    Article  PubMed  Google Scholar 

  14. Masetti M, Carriero R, Portale F, Marelli G, Morina N, Pandini M, et al. Lipid-loaded tumor-associated macrophages sustain tumor growth and invasiveness in prostate cancer. J Exp Med. 2022;219:e20210564.

    Article  CAS  PubMed  Google Scholar 

  15. Timperi E, Gueguen P, Molgora M, Magagna I, Kieffer Y, Lopez-Lastra S, et al. Lipid-associated macrophages are induced by cancer-associated fibroblasts and mediate immune suppression in breast cancer. Cancer Res. 2022;82:3291–306.

    Article  CAS  PubMed  Google Scholar 

  16. Su P, Wang Q, Bi E, Ma X, Liu L, Yang M, et al. Enhanced lipid accumulation and metabolism are required for the differentiation and activation of tumor-associated macrophages. Cancer Res. 2020;80:1438–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Di Conza G, Tsai C-H, Gallart-Ayala H, Yu Y-R, Franco F, Zaffalon L, et al. Tumor-induced reshuffling of lipid composition on the endoplasmic reticulum membrane sustains macrophage survival and pro-tumorigenic activity. Nat Immunol. 2021;22:1403–15.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Marelli G, Morina N, Portale F, Pandini M, Iovino M, Di Conza G, et al. Lipid-loaded macrophages as new therapeutic target in cancer. J Immunother Cancer. 2022;10:e004584.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Wu H, Han Y, Rodriguez Sillke Y, Deng H, Siddiqui S, Treese C, et al. Lipid droplet-dependent fatty acid metabolism controls the immune suppressive phenotype of tumor-associated macrophages. EMBO Mol Med. 2019;11:e10698.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. El-Serag HB. Hepatocellular carcinoma. N Engl J Med. 2011;365:1118–27.

    Article  CAS  PubMed  Google Scholar 

  21. Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet. 2018;391:1301–14.

    Article  PubMed  Google Scholar 

  22. Ning W-R, Jiang D, Liu X-C, Huang Y-F, Peng Z-P, Jiang Z-Z, et al. Carbonic anhydrase XII mediates the survival and prometastatic functions of macrophages in human hepatocellular carcinoma. J Clin Investig. 2022;132:e153110.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Chen D-P, Ning W-R, Jiang Z-Z, Peng Z-P, Zhu L-Y, Zhuang S-M, et al. Glycolytic activation of peritumoral monocytes fosters immune privilege via the PFKFB3-PD-L1 axis in human hepatocellular carcinoma. J Hepatol. 2019;71:333–43.

    Article  CAS  PubMed  Google Scholar 

  24. Lu L-G, Zhou Z-L, Wang X-Y, Liu B-Y, Lu J-Y, Liu S, et al. PD-L1 blockade liberates intrinsic antitumourigenic properties of glycolytic macrophages in hepatocellular carcinoma. Gut. 2022;71:2551–60.

    Article  CAS  PubMed  Google Scholar 

  25. Peng Z-P, Jiang Z-Z, Guo H-F, Zhou M-M, Huang Y-F, Ning W-R, et al. Glycolytic activation of monocytes regulates the accumulation and function of neutrophils in human hepatocellular carcinoma. J Hepatol. 2020;73:906–17.

    Article  CAS  PubMed  Google Scholar 

  26. Li Z, Wang Y, Xing R, Zeng H, Yu X-J, Zhang Y, et al. Cholesterol efflux drives the generation of immunosuppressive macrophages to promote the progression of human hepatocellular carcinoma. Cancer Immunol Res. 2023;11:1400–13.

    Article  CAS  PubMed  Google Scholar 

  27. Jaitin DA, Adlung L, Thaiss CA, Weiner A, Li B, Descamps H, et al. Lipid-associated macrophages control metabolic homeostasis in a Trem2-dependent manner. Cell. 2019;178:686–98.e14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Kuang D-M, Zhao Q, Wu Y, Peng C, Wang J, Xu Z, et al. Peritumoral neutrophils link inflammatory response to disease progression by fostering angiogenesis in hepatocellular carcinoma. J Hepatol. 2011;54:948–55.

    Article  CAS  PubMed  Google Scholar 

  29. Ogretmen B. Sphingolipid metabolism in cancer signaling and therapy. Nat Rev Cancer. 2018;18:33–50.

    Article  CAS  PubMed  Google Scholar 

  30. Liu X, Hartman CL, Li L, Albert CJ, Si F, Gao A, et al. Reprogramming lipid metabolism prevents effector T-cell senescence and enhances tumor immunotherapy. Sci Transl Med. 2021;13:eaaz6314.

    Article  CAS  PubMed  Google Scholar 

  31. Luo Q, Zheng N, Jiang L, Wang T, Zhang P, Liu Y, et al. Lipid accumulation in macrophages confers protumorigenic polarization and immunity in gastric cancer. Cancer Sci. 2020;111:4000–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Kruth HS. Receptor-independent fluid-phase pinocytosis mechanisms for induction of foam cell formation with native low-density lipoprotein particles. Curr Opin Lipido. 2011;22:386–93.

    Article  CAS  Google Scholar 

  33. Kuang D-M, Xiao X, Zhao Q, Chen M-M, Li X-F, Liu R-X, et al. B7-H1–expressing antigen-presenting cells mediate polarization of protumorigenic Th22 subsets. J Clin Invest. 2014;124:4657–67.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Kuang D-M, Zhao Q, Xu J, Yun J-P, Wu C, Zheng L. Tumor-educated tolerogenic dendritic cells induce CD3epsilon downregulation and apoptosis of T cells through oxygen-dependent pathways. J Immunol. 2008;181:3089–98.

    Article  CAS  PubMed  Google Scholar 

  35. Kuang D-M, Peng C, Zhao Q, Wu Y, Chen M-S, Zheng L. Activated monocytes in peritumoral stroma of hepatocellular carcinoma promote expansion of memory T helper 17 cells. Hepatology. 2010;51:154–64.

    Article  CAS  PubMed  Google Scholar 

  36. Meitei HT, Jadhav N, Lal G. CCR6-CCL20 axis as a therapeutic target for autoimmune diseases. Autoimmun Rev. 2021;20:102846.

    Article  CAS  PubMed  Google Scholar 

  37. Peng Y, Tao Y, Zhang Y, Wang J, Yang J, Wang Y. CD25: A potential tumor therapeutic target. Int J Cancer. 2023;152:1290–303.

    Article  CAS  PubMed  Google Scholar 

  38. Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol. 1995;155:1151–64.

    Article  CAS  PubMed  Google Scholar 

  39. Donadon M, Torzilli G, Cortese N, Soldani C, Di Tommaso L, Franceschini B, et al. Macrophage morphology correlates with single-cell diversity and prognosis in colorectal liver metastasis. J Exp Med. 2020;217:e20191847.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Park MD, Reyes-Torres I, LeBerichel J, Hamon P, LaMarche NM, Hegde S, et al. TREM2 macrophages drive NK cell paucity and dysfunction in lung cancer. Nat Immunol. 2023;24:792–801.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Keigo K, Masafumi M, Sachiko F, Haque ASMR, Yasuyuki M, Teppei J, et al. CD163+CD204+ tumor-associated macrophages contribute to T-cell regulation via interleukin-10 and PD-L1 production in oral squamous cell carcinoma. Sci Rep. 2017;7:1755.

    Article  Google Scholar 

  42. Niu Z, Shi Q, Zhang W, Shu Y, Yang N, Chen B, et al. Caspase-1 cleaves PPARγ for potentiating the pro-tumor action of TAMs. Nat Commun. 2017;8:766.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Huggins DN, LaRue RS, Wang Y, Knutson TP, Xu Y, Williams JW, et al. Characterizing macrophage diversity in metastasis-bearing lungs reveals a lipid-associated macrophage subset. Cancer Res. 2021;81:5284–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Govaere O, Petersen SK, Martinez-Lopez N, Wouters J, Van Haele M, Mancina RM, et al. Macrophage scavenger receptor 1 mediates lipid-induced inflammation in nonalcoholic fatty liver disease. J Hepatol. 2022;76:1001–12.

    Article  CAS  PubMed  Google Scholar 

  45. Henne WM, Reese ML, Goodman JM. The assembly of lipid droplets and their roles in challenged cells. EMBO J. 2018;37:e98947.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Almeida PED, Toledo DAM, Rodrigues GSC, D’Avila H. Lipid bodies as sites of prostaglandin E2 synthesis during chagas disease: Impact in the parasite escape mechanism. Front Microbiol. 2018;9:499.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Guijas C, Pérez-Chacón G, Astudillo AM, Rubio JM, Gil-de-Gómez L, Balboa MA, et al. Simultaneous activation of p38 and JNK by arachidonic acid stimulates the cytosolic phospholipase A2-dependent synthesis of lipid droplets in human monocytes. J Lipid Res. 2012;53:2343–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Cotte AK, Aires V, Fredon M, Limagne E, Derangère V, Thibaudin M, et al. Lysophosphatidylcholine acyltransferase 2-mediated lipid droplet production supports colorectal cancer chemoresistance. Nat Commun. 2018;9:322.

    Article  PubMed  PubMed Central  Google Scholar 

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Funding

This work was supported by project grants from the National Key R&D Program of China (2023YFA0915703), the Guangdong Basic and Applied Basic Research Foundation (2022A1515111205), the National Natural Science Foundation of China (32230034, 82273296), and the Open Fund Project of Guangdong Academy of Medical Sciences (YKY-KF202207).

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Author notes

  1. These authors contributed equally: Yongchun Wang, Weibai Chen.

Authors and Affiliations

  1. Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, PR China

    Yongchun Wang, Weibai Chen, Shuang Qiao, Hao Zou, Xing-juan Yu, Zhixiong Li, Junfeng Wang, Min-shan Chen, Jing Xu & Limin Zheng

  2. Key Laboratory of Gene Function and Regulation of the Ministry of Education, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, PR China

    Yongchun Wang, Weibai Chen, Yanyan Yang & Limin Zheng

  3. Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, PR China

    Min-shan Chen

Authors
  1. Yongchun Wang
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Contributions

Y Wang: Formal analysis, investigation, methodology, project administration, writing–review and editing. W Chen: Validation, investigation, methodology, project administration. S Qiao: Methodology, investigation. H Zou: Methodology and project administration. X Yu: Resources. Y Yang: Investigation. Z Li: Methodology. J Wang: Methodology. M Chen: Resources. J Xu: Methodology, writing–review and editing. L Zheng: Project administration, writing–review and editing.

Corresponding authors

Correspondence to Jing Xu or Limin Zheng.

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The authors declare no competing interests. L Zheng is an editorial board member of Cellular & Molecular Immunology, but he has not been involved in the peer review of or decision-making regarding the article.

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Wang, Y., Chen, W., Qiao, S. et al. Lipid droplet accumulation mediates macrophage survival and Treg recruitment via the CCL20/CCR6 axis in human hepatocellular carcinoma. Cell Mol Immunol 21, 1120–1130 (2024). https://doi.org/10.1038/s41423-024-01199-x

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