Research ArticleOriginal Article

Panoramic comparison between NK cells in healthy and cancerous liver through single-cell RNA sequencing

Huan Liu, Ronghua Zhao, Rongrong Qin, Haoyu Sun, Qiang Huang, Lianxin Liu, Zhigang Tian, Björn Nashan, Cheng Sun and Rui Sun
Cancer Biology & Medicine September 2022, 19 (9) 1334-1351; DOI: https://doi.org/10.20892/j.issn.2095-3941.2022.0050

References

  1. 1.↵
    2. Vivier E,
    3. Artis D,
    4. Colonna M,
    5. Diefenbach A,
    6. Di Santo JP,
    7. Eberl G, et al.
    Innate Lymphoid Cells: 10 Years On. Cell. 2018; 174: 1054–66.
    OpenUrlCrossRefPubMed
  2. 2.↵
    2. Mace EM,
    3. Orange JS.
    Emerging insights into human health and NK cell biology from the study of NK cell deficiencies. Immunol Rev. 2019; 287: 202–25.
    OpenUrlCrossRefPubMed
  3. 3.↵
    2. Sun JC,
    3. Lanier LL.
    NK cell development, homeostasis and function: parallels with CD8(+) T cells. Nat Rev Immunol. 2011; 11: 645–57.
    OpenUrlCrossRefPubMed
  4. 4.↵
    2. Zhang Q,
    3. Bi J,
    4. Zheng X,
    5. Chen Y,
    6. Wang H,
    7. Wu W, et al.
    Blockade of the checkpoint receptor TIGIT prevents NK cell exhaustion and elicits potent anti-tumor immunity. Nat Immunol. 2018; 19: 723–32.
    OpenUrlCrossRefPubMed
  5. 5.↵
    2. Zhang C,
    3. Hu Y,
    4. Xiao W,
    5. Tian Z.
    Chimeric antigen receptor- and natural killer cell receptor-engineered innate killer cells in cancer immunotherapy. Cell Mol Immunol. 2021; 18: 2083–100.
    OpenUrl
  6. 6.
    2. Xue W,
    3. Zhang M.
    Updating targets for natural killer/T-cell lymphoma immunotherapy. Cancer Biol Med. 2021; 18: 52–62.
    OpenUrlAbstract/FREE Full Text
  7. 7.
    2. Xu Z,
    3. Huang X.
    Cellular immunotherapy for hematological malignancy: recent progress and future perspectives. Cancer Biol Med. 2021; 18: 966–80.
    OpenUrlAbstract/FREE Full Text
  8. 8.↵
    2. Ruf B,
    3. Heinrich B,
    4. Greten TF.
    Immunobiology and immunotherapy of HCC: spotlight on innate and innate-like immune cells. Cell Mol Immunol. 2021; 18: 112–27.
    OpenUrlPubMed
  9. 9.↵
    2. Fang F,
    3. Xie S,
    4. Chen M,
    5. Li Y,
    6. Yue J,
    7. Ma J, et al.
    Advances in NK cell production. Cell Mol Immunol. 2022; 19: 460–81.
    OpenUrl
  10. 10.↵
    2. Freud AG,
    3. Mundy-Bosse BL,
    4. Yu J,
    5. Caligiuri MA.
    The Broad Spectrum of Human Natural Killer Cell Diversity. Immunity. 2017; 47: 820–33.
    OpenUrlCrossRefPubMed
  11. 11.↵
    2. Doherty DG,
    3. Norris S,
    4. Madrigal-Estebas L,
    5. McEntee G,
    6. Traynor O,
    7. Hegarty JE.
    The human liver contains multiple populations of NK cells, T cells, and CD3+CD56+ natural T cells with distinct cytotoxic activities and T1, T2, and T0 cytokine secretion patterns. J Immunol. 1999; 163: 2314–21.
    OpenUrlAbstract/FREE Full Text
  12. 12.↵
    2. Doherty DG,
    3. O’Farrelly C.
    Innate and adaptive lymphoid cells in the human liver. Immunol Rev. 2000; 174: 5–20.
    OpenUrlCrossRefPubMedWeb of Science
  13. 13.↵
    2. Ahmed O,
    3. Robinson MW,
    4. O’Farrelly C.
    Inflammatory processes in the liver: divergent roles in homeostasis and pathology. Cell Mol Immunol. 2021; 18: 1375–86.
    OpenUrl
  14. 14.↵
    2. Peng H,
    3. Jiang X,
    4. Chen Y,
    5. Sojka DK,
    6. Wei H,
    7. Gao X, et al.
    Liver-resident NK cells confer adaptive immunity in skin-contact inflammation. J Clin Invest. 2013; 123: 1444–56.
    OpenUrlCrossRefPubMed
  15. 15.↵
    2. Lunemann S,
    3. Martrus G,
    4. Goebels H,
    5. Kautz T,
    6. Langeneckert A,
    7. Salzberger W, et al.
    Hobit expression by a subset of human liver-resident CD56(bright) Natural Killer cells. Sci Rep. 2017; 7: 6676.
    OpenUrlPubMed
  16. 16.
    2. Stegmann KA,
    3. Robertson F,
    4. Hansi N,
    5. Gill U,
    6. Pallant C,
    7. Christophides T, et al.
    CXCR6 marks a novel subset of T-bet(lo)Eomes(hi) natural killer cells residing in human liver. Sci Rep. 2016; 6: 26157.
  17. 17.↵
    2. Harmon C,
    3. Robinson MW,
    4. Fahey R,
    5. Whelan S,
    6. Houlihan DD,
    7. Geoghegan J, et al.
    Tissue-resident Eomes(hi) T-bet(lo) CD56(bright) NK cells with reduced proinflammatory potential are enriched in the adult human liver. Eur J Immunol. 2016; 46: 2111–20.
    OpenUrl
  18. 18.↵
    2. Aw Yeang HX,
    3. Piersma SJ,
    4. Lin Y,
    5. Yang L,
    6. Malkova ON,
    7. Miner C, et al.
    Cutting Edge: Human CD49e- NK Cells Are Tissue Resident in the Liver. J Immunol. 2017; 198: 1417–22.
    OpenUrlAbstract/FREE Full Text
  19. 19.↵
    2. Hudspeth K,
    3. Donadon M,
    4. Cimino M,
    5. Pontarini E,
    6. Tentorio P,
    7. Preti M, et al.
    Human liver-resident CD56(bright)/CD16(neg) NK cells are retained within hepatic sinusoids via the engagement of CCR5 and CXCR6 pathways. J Autoimmun. 2016; 66: 40–50.
    OpenUrlCrossRefPubMed
  20. 20.↵
    2. Sun Y,
    3. Zhou J,
    4. Fan J,
    5. Yang X.
    Single-cell RNA sequencing reveals spatial heterogeneity and immune evasion of circulating tumor cells. Cancer Biology & Medicine. 2021; 18: 934–6.
    OpenUrl
  21. 21.
    2. Wang L,
    3. Mo S,
    4. Li X,
    5. He Y,
    6. Yang J.
    Single-cell RNA-seq reveals the immune escape and drug resistance mechanisms of mantle cell lymphoma. Cancer Biol Med. 2020; 17: 726–39.
    OpenUrlAbstract/FREE Full Text
  22. 22.↵
    2. Papalexi E,
    3. Satija R.
    Single-cell RNA sequencing to explore immune cell heterogeneity. Nat Rev Immunol. 2018; 18: 35–45.
    OpenUrlPubMed
  23. 23.↵
    2. Yang C,
    3. Siebert JR,
    4. Burns R,
    5. Gerbec ZJ,
    6. Bonacci B,
    7. Rymaszewski A, et al.
    Heterogeneity of human bone marrow and blood natural killer cells defined by single-cell transcriptome. Nat Commun. 2019; 10: 3931.
    OpenUrlCrossRefPubMed
  24. 24.↵
    2. Smith SL,
    3. Kennedy PR,
    4. Stacey KB,
    5. Worboys JD,
    6. Yarwood A,
    7. Seo S, et al.
    Diversity of peripheral blood human NK cells identified by single-cell RNA sequencing. Blood Adv. 2020; 4: 1388–406.
    OpenUrlCrossRefPubMed
  25. 25.↵
    2. Crinier A,
    3. Milpied P,
    4. Escaliere B,
    5. Piperoglou C,
    6. Galluso J,
    7. Balsamo A, et al.
    High-Dimensional Single-Cell Analysis Identifies Organ-Specific Signatures and Conserved NK Cell Subsets in Humans and Mice. Immunity. 2018; 49: 971–86 e5.
    OpenUrlCrossRefPubMed
  26. 26.↵
    2. Bray F,
    3. Ferlay J,
    4. Soerjomataram I,
    5. Siegel RL,
    6. Torre LA,
    7. Jemal A.
    Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018; 68: 394–424.
    OpenUrlCrossRefPubMed
  27. 27.↵
    2. Sun D,
    3. Li H,
    4. Cao M,
    5. He S,
    6. Lei L,
    7. Peng J, et al.
    Cancer burden in China: trends, risk factors and prevention. Cancer Biol Med. 2020; 17: 879–95.
    OpenUrlAbstract/FREE Full Text
  28. 28.↵
    2. Villanueva A.
    Hepatocellular Carcinoma. N Engl J Med. 2019; 380: 1450–62.
    OpenUrlCrossRefPubMed
  29. 29.↵
    2. MacParland SA,
    3. Liu JC,
    4. Ma XZ,
    5. Innes BT,
    6. Bartczak AM,
    7. Gage BK, et al.
    Single cell RNA sequencing of human liver reveals distinct intrahepatic macrophage populations. Nat Commun. 2018; 9: 4383.
    OpenUrlCrossRefPubMed
  30. 30.↵
    2. Zhao J,
    3. Zhang S,
    4. Liu Y,
    5. He X,
    6. Qu M,
    7. Xu G, et al.
    Single-cell RNA sequencing reveals the heterogeneity of liver-resident immune cells in human. Cell Discovery. 2020; 6: 22.
    OpenUrl
  31. 31.↵
    2. Sun Y,
    3. Wu L,
    4. Zhong Y,
    5. Zhou K,
    6. Hou Y,
    7. Wang Z, et al.
    Single-cell landscape of the ecosystem in early-relapse hepatocellular carcinoma. Cell. 2021; 184: 404–21 e16.
    OpenUrlPubMed
  32. 32.↵
    2. Zhang Q,
    3. He Y,
    4. Luo N,
    5. Patel SJ,
    6. Han Y,
    7. Gao R, et al.
    Landscape and Dynamics of Single Immune Cells in Hepatocellular Carcinoma. Cell. 2019; 179: 829–45 e20.
    OpenUrlCrossRefPubMed
  33. 33.↵
    2. Stuart T,
    3. Butler A,
    4. Hoffman P,
    5. Hafemeister C,
    6. Papalexi E,
    7. Mauck WM, 3rd., et al.
    Comprehensive Integration of Single-Cell Data. Cell. 2019; 177: 1888–902 e21.
    OpenUrlCrossRefPubMed
  34. 34.↵
    2. Butler A,
    3. Hoffman P,
    4. Smibert P,
    5. Papalexi E,
    6. Satija R.
    Integrating single-cell transcriptomic data across different conditions, technologies, and species. Nat Biotechnol. 2018; 36: 411–20.
    OpenUrlCrossRefPubMed
  35. 35.↵
    2. Mazzurana L,
    3. Czarnewski P,
    4. Jonsson V,
    5. Wigge L,
    6. Ringner M,
    7. Williams TC, et al.
    Tissue-specific transcriptional imprinting and heterogeneity in human innate lymphoid cells revealed by full-length single-cell RNA-sequencing. Cell Res. 2021; 31: 554–68.
    OpenUrlCrossRef
  36. 36.↵
    2. Bjorklund AK,
    3. Forkel M,
    4. Picelli S,
    5. Konya V,
    6. Theorell J,
    7. Friberg D, et al.
    The heterogeneity of human CD127(+) innate lymphoid cells revealed by single-cell RNA sequencing. Nat Immunol. 2016; 17: 451–60.
    OpenUrlCrossRefPubMed
  37. 37.↵
    2. Traag VA,
    3. Waltman L,
    4. van Eck NJ.
    From Louvain to Leiden: guaranteeing well-connected communities. Sci Rep. 2019; 9: 5233.
    OpenUrlCrossRefPubMed
  38. 38.↵
    2. Haghverdi L,
    3. Lun ATL,
    4. Morgan MD,
    5. Marioni JC.
    Batch effects in single-cell RNA-sequencing data are corrected by matching mutual nearest neighbors. Nat Biotechnol. 2018; 36: 421–7.
    OpenUrlCrossRefPubMed
  39. 39.↵
    2. Scheiter M,
    3. Lau U,
    4. van Ham M,
    5. Bulitta B,
    6. Grobe L,
    7. Garritsen H, et al.
    Proteome analysis of distinct developmental stages of human natural killer (NK) cells. Mol Cell Proteomics. 2013; 12: 1099–114.
    OpenUrlAbstract/FREE Full Text
  40. 40.↵
    2. Yu J,
    3. Mao HC,
    4. Wei M,
    5. Hughes T,
    6. Zhang J,
    7. Park IK, et al.
    CD94 surface density identifies a functional intermediary between the CD56bright and CD56dim human NK-cell subsets. Blood. 2010; 115: 274–81.
    OpenUrlAbstract/FREE Full Text
  41. 41.↵
    2. Erokhina SA,
    3. Streltsova MA,
    4. Kanevskiy LM,
    5. Grechikhina MV,
    6. Sapozhnikov AM,
    7. Kovalenko EI.
    HLA-DR-expressing NK cells: Effective killers suspected for antigen presentation. J Leukoc Biol. 2021; 109: 327–37.
    OpenUrl
  42. 42.↵
    2. Erokhina SA,
    3. Streltsova MA,
    4. Kanevskiy LM,
    5. Telford WG,
    6. Sapozhnikov AM,
    7. Kovalenko EI.
    HLA-DR(+) NK cells are mostly characterized by less mature phenotype and high functional activity. Immunol Cell Biol. 2018; 96: 212–28.
    OpenUrl
  43. 43.↵
    2. Hanna J,
    3. Bechtel P,
    4. Zhai Y,
    5. Youssef F,
    6. McLachlan K,
    7. Mandelboim O.
    Novel insights on human NK cells’ immunological modalities revealed by gene expression profiling. J Immunol. 2004; 173: 6547–63.
    OpenUrlAbstract/FREE Full Text
  44. 44.↵
    2. Sun H,
    3. Liu L,
    4. Huang Q,
    5. Liu H,
    6. Huang M,
    7. Wang J, et al.
    Accumulation of Tumor-Infiltrating CD49a(+) NK Cells Correlates with Poor Prognosis for Human Hepatocellular Carcinoma. Cancer Immunol Res. 2019; 7: 1535–46.
    OpenUrlAbstract/FREE Full Text
  45. 45.↵
    2. Pan D,
    3. Kobayashi A,
    4. Jiang P,
    5. Ferrari de Andrade L,
    6. Tay RE,
    7. Luoma AM, et al.
    A major chromatin regulator determines resistance of tumor cells to T cell-mediated killing. Science. 2018; 359: 770–5.
    OpenUrlAbstract/FREE Full Text
  46. 46.↵
    2. Paijens ST,
    3. Vledder A,
    4. de Bruyn M,
    5. Nijman HW.
    Tumor-infiltrating lymphocytes in the immunotherapy era. Cell Mol Immunol. 2021; 18: 842–59.
    OpenUrlPubMed
  47. 47.↵
    2. Zhang Y,
    3. Zhang Z.
    The history and advances in cancer immunotherapy: understanding the characteristics of tumor-infiltrating immune cells and their therapeutic implications. Cell Mol Immunol. 2020; 17: 807–21.
    OpenUrlPubMed
  48. 48.↵
    2. Aizarani N,
    3. Saviano A,
    4. Sagar X,
    5. Mailly L,
    6. Durand S,
    7. Herman JS, et al.
    A human liver cell atlas reveals heterogeneity and epithelial progenitors. Nature. 2019; 572: 199–204.
    OpenUrlCrossRefPubMed
  49. 49.↵
    2. Wang L,
    3. Li J,
    4. He S,
    5. Liu Y,
    6. Chen H,
    7. He S, et al.
    Resolving the graft ischemia-reperfusion injury during liver transplantation at the single cell resolution. Cell Death Dis. 2021; 12: 589.
    OpenUrl
  50. 50.↵
    2. Sun C,
    3. Xu J,
    4. Huang Q,
    5. Huang M,
    6. Wen H,
    7. Zhang C, et al.
    High NKG2A expression contributes to NK cell exhaustion and predicts a poor prognosis of patients with liver cancer. Oncoimmunology. 2017; 6: e1264562.
  51. 51.↵
    2. Sun H,
    3. Huang Q,
    4. Huang M,
    5. Wen H,
    6. Lin R,
    7. Zheng M, et al.
    Human CD96 Correlates to Natural Killer Cell Exhaustion and Predicts the Prognosis of Human Hepatocellular Carcinoma. Hepatology. 2019; 70: 168–83.
    OpenUrlPubMed
  52. 52.↵
    2. Yu L,
    3. Liu X,
    4. Wang X,
    5. Yan F,
    6. Wang P,
    7. Jiang Y, et al.
    TIGIT(+) TIM-3(+) NK cells are correlated with NK cell exhaustion and disease progression in patients with hepatitis B virusrelated hepatocellular carcinoma. Oncoimmunology. 2021; 10: 1942673.
  53. 53.↵
    2. Jameson G,
    3. Robinson MW.
    Insights Into Human Intrahepatic NK Cell Function From Single Cell RNA Sequencing Datasets. Front Immunol. 2021; 12: 649311.
  54. 54.↵
    2. Han J,
    3. Chen C,
    4. Wang C,
    5. Qin N,
    6. Huang M,
    7. Ma Z, et al.
    Transcriptome-wide association study for persistent hepatitis B virus infection and related hepatocellular carcinoma. Liver Int. 2020; 40: 2117–27.
    OpenUrl
  55. 55.↵
    2. Wang XK,
    3. Liao XW,
    4. Yang CK,
    5. Yu TD,
    6. Liu ZQ,
    7. Gong YZ, et al.
    Diagnostic and prognostic biomarkers of Human Leukocyte Antigen complex for hepatitis B virus-related hepatocellular carcinoma. J Cancer. 2019; 10: 5173–90.
    OpenUrl
Back to top

In this issue

Print
Download PDF
Email Article
Citation Tools

Jump to section

Keywords