HCC-Derived Exosomes: Critical Player and Target for Cancer Immune Escape
Abstract
:1. Introduction
2. Characteristics of HCC-Derived Exosomes
3. HCC-Derived Exosomes are Critical for Immune Escape
3.1. Monocytes or Macrophages
3.2. Neutrophils
3.3. Dendritic Cells (DCs)
3.4. Natural Killer (NK) Cells
3.5. T-Cells
3.5.1. CD4+ T-Cells
3.5.2. CD8+ T-Cells
3.6. B-Cells
4. Conclusions and Outlook
Author Contributions
Funding
Conflicts of Interest
References
- Villalba, M.; Rathore, M.G.; López-Royuela, N.; Krzywinska, E.; Garaude, J.; Allende-Vega, N. From tumor cell metabolism to tumor immune escape. Int. J. Biochem. Cell Boil. 2013, 45, 106–113. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Rani, S.; O’Brien, K.; Kelleher, F.C.; Corcoran, C.; Germano, S.; Radomski, M.W.; Crown, J.; O’Driscoll, L. Isolation of exosomes for subsequent mRNA, MicroRNA, and protein profiling. Gene expr. Profiling 2011, 784, 181–195. [Google Scholar]
- Wortzel, I.; Dror, S.; Kenific, C.M.; Lyden, D. Exosome-Mediated Metastasis: Communication from a Distance. Dev. Cell 2019, 49, 347–360. [Google Scholar] [CrossRef] [PubMed]
- Liu, Y.; Gu, Y.; Cao, X. The exosomes in tumor immunity. Oncoimmunology 2015, 4, e1027472. [Google Scholar] [CrossRef] [Green Version]
- Yu, S.; Liu, C.; Su, K.; Wang, J.; Liu, Y.; Zhang, L.; Li, C.; Cong, Y.; Kimberly, R.; Grizzle, W.E.; et al. Tumor Exosomes Inhibit Differentiation of Bone Marrow Dendritic Cells. J. Immunol. 2007, 178, 6867–6875. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Peinado, H.; Alečković, M.; Lavotshkin, S.; Matei, I.; Costa-Silva, B.; Moreno-Bueno, G.; Hergueta-Redondo, M.; Williams, C.; García-Santos, G.; Ghajar, C.M.; et al. Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat. Med. 2012, 18, 883–891. [Google Scholar] [CrossRef] [Green Version]
- Cheng, W.; Liao, T.; Lin, C.; Yuan, L.E.; Lan, H.; Lin, H.; Teng, H.; Chang, H.; Lin, C.; Yang, C.; et al. RAB27B-activated secretion of stem-like tumor exosomes delivers the biomarker microRNA-146a-5p, which promotes tumorigenesis and associates with an immunosuppressive tumor microenvironment in colorectal cancer. Int. J. Cancer 2019. [Google Scholar] [CrossRef]
- Wei, Y.; Wang, D.; Jin, F.; Bian, Z.; Li, L.; Liang, H.; Li, M.; Shi, L.; Pan, C.; Zhu, D.; et al. Pyruvate kinase type M2 promotes tumour cell exosome release via phosphorylating synaptosome-associated protein 23. Nat. Commun. 2017, 8, 14041. [Google Scholar] [Green Version]
- Kogure, T.; Lin, W.-L.; Yan, I.K.; Braconi, C.; Patel, T. Inter-cellular nanovesicle mediated microRNA transfer: A mechanism of environmental modulation of hepatocellular cancer cell growth. Hepatology 2011, 54, 1237–1248. [Google Scholar] [CrossRef]
- He, M.; Qin, H.; Poon, T.C.; Sze, S.-C.; Ding, X.; Na Co, N.; Ngai, S.-M.; Chan, T.-F.; Wong, N. Hepatocellular carcinoma-derived exosomes promote motility of immortalized hepatocyte through transfer of oncogenic proteins and RNAs. CARCIN 2015, 36, 1008–1018. [Google Scholar] [CrossRef] [Green Version]
- Valadi, H.; Ekström, K.; Bossios, A.; Sjöstrand, M.; Lee, J.J.; Lötvall, J.O. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat. Cell Biol. 2007, 9, 654–659. [Google Scholar] [CrossRef] [Green Version]
- Matsuura, Y.; Wada, H.; Eguchi, H.; Gotoh, K.; Kobayashi, S.; Kinoshita, M.; Kubo, M.; Hayashi, K.; Iwagami, Y.; Yamada, D.; et al. Exosomal miR-155 Derived from Hepatocellular Carcinoma Cells Under Hypoxia Promotes Angiogenesis in Endothelial Cells. Am. J. Dig. Dis. 2018, 64, 792–802. [Google Scholar] [CrossRef]
- Yu, L.-X.; Zhang, B.-L.; Yang, Y.; Wang, M.-C.; Lei, G.-L.; Gao, Y.; Liu, H.; Xiao, C.-H.; Xu, J.-J.; Qin, H.; et al. Exosomal microRNAs as potential biomarkers for cancer cell migration and prognosis in hepatocellular carcinoma patient-derived cell models. Oncol. Rep. 2018, 41, 257–269. [Google Scholar] [CrossRef] [Green Version]
- Pozza, E.D.; Forciniti, S.; Palmieri, M.; Dando, I. Secreted molecules inducing epithelial-to-mesenchymal transition in cancer development. Semin. Cell Dev. Boil. 2018, 78, 62–72. [Google Scholar] [CrossRef]
- Song, X.; Ding, Y.; Liu, G.; Yang, X.; Zhao, R.; Zhang, Y.; Zhao, X.; Anderson, G.J.; Nie, G. Cancer Cell-derived Exosomes Induce Mitogen-activated Protein Kinase-dependent Monocyte Survival by Transport of Functional Receptor Tyrosine Kinases. J. Boil. Chem. 2016, 291, 8453–8464. [Google Scholar] [CrossRef] [Green Version]
- Yin, Z.; Ma, T.; Lin, Y.; Lu, X.; Zhang, C.; Chen, S.; Jian, Z. IL-6/STAT3 pathway intermediates M1/M2 macrophage polarization during the development of hepatocellular carcinoma. J. Cell. Biochem. 2018, 119, 9419–9432. [Google Scholar] [CrossRef]
- Ye, Y.; Xu, Y.; Lai, Y.; He, W.; Li, Y.; Wang, R.; Luo, X.; Chen, R.; Chen, T. Long non-coding RNA cox-2 prevents immune evasion and metastasis of hepatocellular carcinoma by altering M1/M2 macrophage polarization. J. Cell. Biochem. 2018, 119, 2951–2963. [Google Scholar] [CrossRef]
- Kogure, T.; Yan, I.K.; Lin, W.L.; Patel, T. Extracellular Vesicle-Mediated Transfer of a Novel Long Noncoding RNA TUC339: A Mechanism of Intercellular Signaling in Human Hepatocellular Cancer. Genes Cancer 2013, 4, 261–272. [Google Scholar] [CrossRef] [Green Version]
- Li, X.; Lei, Y.; Wu, M.; Li, N. Regulation of Macrophage Activation and Polarization by HCC-Derived Exosomal lncRNA TUC. Int. J. Mol. Sci. 2018, 19, 2958. [Google Scholar] [CrossRef]
- Liu, Y.; Zhao, L.; Li, D.; Yin, Y.; Zhang, C.-Y.; Li, J.; Zhang, Y. Microvesicle-delivery miR-150 promotes tumorigenesis by upregulating VEGF, and the neutralization of miR-150 attenuate tumor development. Protein Cell 2013, 4, 932–941. [Google Scholar] [CrossRef]
- Cheng, L.; Liu, J.; Liu, Q.; Liu, Y.; Fan, L.; Wang, F.; Yu, H.; Li, Y.; Bu, L.; Li, X.; et al. Exosomes from Melatonin Treated Hepatocellularcarcinoma Cells Alter the Immunosupression Status through STAT3 Pathway in Macrophages. Int. J. Boil. Sci. 2017, 13, 723–734. [Google Scholar] [CrossRef] [Green Version]
- Liu, J.; Fan, L.; Yu, H.; Zhang, J.; He, Y.; Feng, D.; Wang, F.; Li, X.; Liu, Q.; Li, Y.; et al. Endoplasmic Reticulum Stress Promotes Liver Cancer Cells to Release Exosomal miR-23a-3p and Upregulate PD-L1 Expression in Macrophages. Hepatology 2019. [Google Scholar] [CrossRef]
- Yin, C.; Han, Q.; Xu, D.; Zheng, B.; Zhao, X.; Zhang, J. SALL4-mediated upregulation of exosomal miR-146a-5p drives T-cell exhaustion by M2 tumor-associated macrophages in HCC. OncoImmunology 2019, 8, 1–13. [Google Scholar] [CrossRef]
- Hurt, B.; Schulick, R.; Edil, B.; El Kasmi, K.C.; Barnett, C. Cancer-promoting mechanisms of tumor-associated neutrophils. Am. J. Surg. 2017, 214, 938–944. [Google Scholar] [CrossRef]
- Houghton, A.M.; Rzymkiewicz, D.M.; Ji, H.; Gregory, A.D.; Egea, E.E.; Metz, H.E.; Stolz, D.B.; Land, S.R.; Marconcini, L.A.; Kliment, C.R.; et al. Neutrophil elastase–mediated degradation of IRS-1 accelerates lung tumor growth. Nat. Med. 2010, 16, 219–223. [Google Scholar] [CrossRef]
- Zhang, X.; Shi, H.; Yuan, X.; Jiang, P.; Qian, H.; Xu, W. Tumor-derived exosomes induce N2 polarization of neutrophils to promote gastric cancer cell migration. Mol. Cancer 2018, 17, 146. [Google Scholar] [CrossRef]
- Liu, Y.; Gu, Y.; Han, Y.; Zhang, Q.; Jiang, Z.; Zhang, X.; Huang, B.; Xu, X.; Zheng, J.; Cao, X. Tumor Exosomal RNAs Promote Lung Pre-metastatic Niche Formation by Activating Alveolar Epithelial TLR3 to Recruit Neutrophils. Cancer Cell 2016, 30, 243–256. [Google Scholar] [CrossRef] [Green Version]
- Hwang, W.-L.; Lan, H.-Y.; Cheng, W.-C.; Huang, S.-C.; Yang, M.-H. Tumor stem-like cell-derived exosomal RNAs prime neutrophils for facilitating tumorigenesis of colon cancer. J. Hematol. Oncol. 2019, 12, 10. [Google Scholar] [CrossRef]
- Yang, N.; Li, S.; Li, G.; Zhang, S.; Tang, X.; Ni, S.; Jian, X.; Xu, C.; Zhu, J.; Lu, M. The role of extracellular vesicles in mediating progression, metastasis and potential treatment of hepatocellular carcinoma. Oncotarget 2017, 8, 3683–3695. [Google Scholar] [CrossRef]
- Haider, C.; Hnat, J.; Wagner, R.; Huber, H.; Timelthaler, G.; Grubinger, M.; Coulouarn, C.; Schreiner, W.; Schlangen, K.; Sieghart, W.; et al. Transforming Growth Factor-beta and Axl Induce CXCL5 and Neutrophil Recruitment in Hepatocellular Carcinoma. Hepatology 2019, 69, 222–236. [Google Scholar] [CrossRef]
- Motta, J.M.; Rumjanek, V.M. Sensitivity of Dendritic Cells to Microenvironment Signals. J. Immunol. 2016, 2016, 1–10. [Google Scholar] [CrossRef] [Green Version]
- Ning, Y.; Shen, K.; Wu, Q.; Sun, X.; Bai, Y.; Xie, Y.; Pan, J.; Qi, C. Tumor exosomes block dendritic cells maturation to decrease the T-cell immune response. Immunol. Lett. 2018, 199, 36–43. [Google Scholar] [CrossRef]
- Robbins, P.D.; Morelli, A.E. Regulation of immune responses by extracellular vesicles. Nat. Rev. Immunol. 2014, 14, 195–208. [Google Scholar] [CrossRef] [Green Version]
- Rao, Q.; Zuo, B.; Lu, Z.; Gao, X.; You, A.; Wu, C.; Du, Z.; Yin, H. Tumor-derived exosomes elicit tumor suppression in murine hepatocellular carcinoma models and humans in vitro. Hepatology 2016, 64, 456–472. [Google Scholar] [CrossRef]
- Zhao, F.; Korangy, F.; Greten, T.F. Cellular Immune Suppressor Mechanisms in Patients with Hepatocellular Carcinoma. Dig. Dis. 2012, 30, 477–482. [Google Scholar] [CrossRef] [Green Version]
- Abel, A.M.; Yang, C.; Thakar, M.S.; Malarkannan, S. Natural Killer Cells: Development, Maturation, and Clinical Utilization. Front. Immunol. 2018, 9, 1869. [Google Scholar] [CrossRef] [Green Version]
- Huyan, T.; Du, Y.; Huang, Q.; Huang, Q.; Li, Q. Uptake Characterization of Tumor Cell-derived Exosomes by Natural Killer Cells. Iran. J. Public Health 2018, 47, 803–813. [Google Scholar]
- Muller, L.; Simms, P.; Hong, C.-S.; Nishimura, M.I.; Jackson, E.K.; Watkins, S.C.; Whiteside, T.L. Human tumor-derived exosomes (TEX) regulate Treg functions via cell surface signaling rather than uptake mechanisms. OncoImmunology 2017, 6, e1261243. [Google Scholar] [CrossRef]
- Elsner, L.; Muppala, V.; Gehrmann, M.; Lozano, J.; Malzahn, D.; Bickeböller, H.; Brunner, E.; Zientkowska, M.; Herrmann, T.; Walter, L.; et al. The Heat Shock Protein HSP70 Promotes Mouse NK Cell Activity against Tumors That Express Inducible NKG2D Ligands. J. Immunol. 2007, 179, 5523–5533. [Google Scholar] [CrossRef]
- Lv, L.-H.; Wan, Y.-L.; Lin, Y.; Zhang, W.; Yang, M.; Li, G.-L.; Lin, H.-M.; Shang, C.-Z.; Chen, Y.-J.; Min, J. Anticancer Drugs Cause Release of Exosomes with Heat Shock Proteins from Human Hepatocellular Carcinoma Cells That Elicit Effective Natural Killer Cell Antitumor Responses in Vitro. J. Boil. Chem. 2012, 287, 15874–15885. [Google Scholar] [CrossRef] [Green Version]
- Schmiedel, D.; Mandelboim, O. NKG2D Ligands–Critical Targets for Cancer Immune Escape and Therapy. Front. Immunol. 2018, 9, 9. [Google Scholar] [CrossRef]
- Ashiru, O.; Boutet, P.; Fernández-Messina, L.; Agüera-González, S.; Skepper, J.N.; Valés-Gómez, M.; Reyburn, H.T. Natural Killer Cell Cytotoxicity Is Suppressed by Exposure to the Human NKG2D Ligand MICA*008 That Is Shed by Tumor Cells in Exosomes. Cancer Res. 2010, 70, 481–489. [Google Scholar] [CrossRef] [Green Version]
- Hedlund, M.; Nagaeva, O.; Kargl, D.; Baranov, V.; Mincheva-Nilsson, L. Thermal- and Oxidative Stress Causes Enhanced Release of NKG2D Ligand-Bearing Immunosuppressive Exosomes in Leukemia/Lymphoma T and B-cells. PLoS ONE 2011, 6, e16899. [Google Scholar] [CrossRef]
- Xiao, W.; Dong, W.; Zhang, C.; Saren, G.; Geng, P.; Zhao, H.; Li, Q.; Zhu, J.; Li, G.; Zhang, S.; et al. Effects of the epigenetic drug MS-275 on the release and function of exosome-related immune molecules in hepatocellular carcinoma cells. Eur. J. Med 2013, 18, 61. [Google Scholar] [CrossRef]
- Yang, Y.; Han, Q.; Hou, Z.; Zhang, C.; Tian, Z.; Zhang, J. Exosomes mediate hepatitis B virus (HBV) transmission and NK-cell dysfunction. Cell. Mol. Immunol. 2017, 14, 465–475. [Google Scholar] [CrossRef]
- Sun, C.; Lan, P.; Han, Q.; Huang, M.; Zhang, Z.; Xu, G.; Song, J.; Wang, J.; Wei, H.; Zhang, J.; et al. Oncofetal gene SALL4 reactivation by hepatitis B virus counteracts miR-200c in PD-L1-induced T-cell exhaustion. Nat. Commun. 2018, 9, 1241. [Google Scholar] [CrossRef]
- Sun, C.; Sun, H.-Y.; Xiao, W.-H.; Zhang, C.; Tian, Z.-G. Natural killer cell dysfunction in hepatocellular carcinoma and NK cell-based immunotherapy. Acta Pharmacol. Sin. 2015, 36, 1191–1199. [Google Scholar] [CrossRef] [Green Version]
- Whiteside, T.L. Immune modulation of T-cell and NK (natural killer) cell activities by TEXs (tumour-derived exosomes). Biochem. Soc. Trans. 2013, 41, 245–251. [Google Scholar] [CrossRef]
- Wang, X.; Shen, H.; Zhangyuan, G.; Huang, R.; Zhang, W.; He, Q.; Jin, K.; Zhuo, H.; Zhang, Z.; Wang, J.; et al. 14-3-3zeta delivered by hepatocellular carcinoma-derived exosomes impaired anti-tumor function of tumor-infiltrating T lymphocytes. Cell Death Dis. 2018, 9, 159. [Google Scholar] [CrossRef]
- Muller, L.; Mitsuhashi, M.; Simms, P.; Gooding, W.E.; Whiteside, T.L. Tumor-derived exosomes regulate expression of immune function-related genes in human T-cell subsets. Sci. Rep. 2016, 6, 20254. [Google Scholar] [CrossRef]
- Crespo, J.; Sun, H.; Welling, T.H.; Tian, Z.; Zou, W. T-cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment. Curr. Opin. Immunol. 2013, 25, 214–221. [Google Scholar] [CrossRef]
- Montes, C.L.; Chapoval, A.I.; Nelson, J.; Orhue, V.; Zhang, X.; Schulze, D.H.; Strome, S.E.; Gastman, B.R. Tumor-induced senescent T-cells with suppressor function: A potential form of tumor immune evasion. Cancer Res. 2008, 68, 870–879. [Google Scholar] [CrossRef]
- Mincheva-Nilsson, L.; Baranov, V. Cancer exosomes and NKG2D receptor–ligand interactions: Impairing NKG2D-mediated cytotoxicity and anti-tumour immune surveillance. Semin. Cancer Boil. 2014, 28, 24–30. [Google Scholar] [CrossRef]
- Chen, G.; Huang, A.C.; Zhang, W.; Zhang, G.; Wu, M.; Xu, W.; Yu, Z.; Yang, J.; Wang, B.; Sun, H.; et al. Exosomal PD-L1 Contributes to Immunosuppression and is Associated with anti-PD-1 Response. Nat. Cell Biol. 2018, 560, 382–386. [Google Scholar] [CrossRef]
- Monypenny, J.; Milewicz, H.; Flores-Borja, F.; Weitsman, G.; Cheung, A.; Chowdhury, R.; Burgoyne, T.; Arulappu, A.; Lawler, K.; Barber, P.R.; et al. ALIX Regulates Tumor-Mediated Immunosuppression by Controlling EGFR Activity and PD-L1 Presentation. Cell Rep. 2018, 24, 630–641. [Google Scholar] [CrossRef] [Green Version]
- Ye, L.; Zhang, Q.; Cheng, Y.; Chen, X.; Wang, G.; Shi, M.; Zhang, T.; Cao, Y.; Pan, H.; Zhang, L.; et al. Tumor-derived exosomal HMGB1 fosters hepatocellular carcinoma immune evasion by promoting TIM-1(+) regulatory B-cell expansion. J. ImmunoTherapy Cancer 2018, 6, 145. [Google Scholar] [CrossRef]
- Shao, Y.; Lo, C.M.; Ling, C.C.; Liu, X.B.; Ng, K.T.-P.; Chu, A.C.Y.; Ma, Y.Y.; Li, C.X.; Fan, S.T.; Man, K. Regulatory B-cells accelerate hepatocellular carcinoma progression via CD40/CD154 signaling pathway. Cancer Lett. 2014, 355, 264–272. [Google Scholar] [CrossRef]
- Xiao, X.; Lao, X.M.; Chen, M.M.; Liu, R.X.; Wei, Y.; Ouyang, F.Z.; Chen, D.P.; Zhao, X.Y.; Zhao, Q.; Li, X.F.; et al. PD-1hi Identifies a Novel Regulatory B-cell Population in Human Hepatoma That Promotes Disease Progression. Cancer Discov. 2016, 6, 546–559. [Google Scholar] [CrossRef]
- Zhang, L.; Yu, D. Exosomes in cancer development, metastasis, and immunity. BBA Rev. Cancer 2019, 1871, 455–468. [Google Scholar] [CrossRef]
- Clayton, A.; Mitchell, J.P.; Court, J.; Linnane, S.; Mason, M.D.; Tabi, Z. Human Tumor-Derived Exosomes Down-Modulate NKG2D Expression. J. Immunol. 2008, 180, 7249–7258. [Google Scholar] [CrossRef] [Green Version]
- Okoye, I.S.; Coomes, S.M.; Pelly, V.S.; Czieso, S.; Papayannopoulos, V.; Tolmachova, T.; Seabra, M.C.; Wilson, M.S. MicroRNA-Containing T-Regulatory-Cell-Derived Exosomes Suppress Pathogenic T Helper 1 Cells. Immunity 2014, 41, 89–103. [Google Scholar] [CrossRef] [Green Version]
© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Han, Q.; Zhao, H.; Jiang, Y.; Yin, C.; Zhang, J. HCC-Derived Exosomes: Critical Player and Target for Cancer Immune Escape. Cells 2019, 8, 558. https://doi.org/10.3390/cells8060558
Han Q, Zhao H, Jiang Y, Yin C, Zhang J. HCC-Derived Exosomes: Critical Player and Target for Cancer Immune Escape. Cells. 2019; 8(6):558. https://doi.org/10.3390/cells8060558
Chicago/Turabian StyleHan, Qiuju, Huajun Zhao, Yu Jiang, Chunlai Yin, and Jian Zhang. 2019. "HCC-Derived Exosomes: Critical Player and Target for Cancer Immune Escape" Cells 8, no. 6: 558. https://doi.org/10.3390/cells8060558