AI Chat Paper
Note: Please note that the following content is generated by AMiner AI. SciOpen does not take any responsibility related to this content.
{{lang === 'zh_CN' ? '文章概述' : 'Summary'}}
{{lang === 'en_US' ? '中' : 'Eng'}}
Chat more with AI
Powered by AMiner. Clicking this button will take you away from SciOpen.
Home Cancer Biology & Medicine Article
PDF (2.4 MB)
Cite
EndNote(RIS) BibTeX
Collect
Submit Manuscript AI Chat Paper
Show Outline
Outline
Show full outline
Hide outline
Outline
Show full outline
Hide outline
Original Article | Open Access

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

Huan Liu1,2,3, Ronghua Zhao1, Rongrong Qin1, Haoyu Sun2,3, Qiang Huang1, Lianxin Liu1, Zhigang Tian2,3, Björn Nashan1, Cheng Sun1,2,3 ( ), Rui Sun2,3 ( )
The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China
The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
Institute of Immunology, University of Science and Technology of China, Hefei 230027, China
Show Author Information

Abstract

Objective

NK cells play crucial roles in the immune defense mechanisms against viral infections and transformed cells. However, the developmental progression, transcriptomic landscape, and functional subtypes of liver NK cells are not well defined. Hepatocellular carcinoma (HCC) accounts for approximately 80% of primary liver cancer worldwide, yet the biological characteristics of NK cells in the HCC environment are unclear. Therefore, we aimed to determine these cells’ roles in tumorigenesis and prognosis.

Methods

We compared the single-cell RNA sequencing profiles of NK cells purified from blood (n = 1), healthy liver tissues (n = 3), HCC tumor tissues (n = 4), and peritumor liver tissues (n = 1) to identify NK cell subsets. Furthermore, we performed bioinformatics analysis by using The Cancer Genome Atlas (TCGA) data to identify prognostic biomarkers simultaneously overexpressed in the blood and tumor tissues of patients with HCC.

Results

Transcriptomic analysis revealed 5 NK cell subsets (L1-NK-CD56bright, L2-NK-CD56dim, L3-NK-HLA, L4-LrNK-FCGR3A, and L5-LrNK-XCL1) in the healthy liver tissues. However, the transitional L3 subset and the CXCR6+CD16+ L4 subset with strong anti-tumor activity were absent in the HCC and peritumor liver tissues. Furthermore, 4 common prognosis-associated genes (RHOB, TALDO1, HLA-DPA1, and TKT) were significantly overexpressed in the paired tumor tissue and blood.

Conclusions

Our study revealed 5 specific subsets of NK cells in healthy human liver tissues. However, only 3 of the 5 NK cell subsets were present in HCC and peritumor tissues. The cytotoxic NK cell subsets were absent in HCC tissues. Furthermore, we identified 4 potential non-invasive prognostic biomarkers in patients with HCC.

Keywords

heterogeneityHepatocellular carcinomaprognosissingle-cell RNA sequencingnatural killer cell

Electronic Supplementary Material

Download File(s)
cbm-19-9-1334_ESM.pdf (721.4 KB)

References

1

Vivier E, Artis D, Colonna M, Diefenbach A, Di Santo JP, Eberl G, et al. Innate Lymphoid Cells: 10 Years On. Cell. 2018; 174: 1054-66.
Crossref Google Scholar
2

Mace EM, Orange JS. Emerging insights into human health and NK cell biology from the study of NK cell deficiencies. Immunol Rev. 2019; 287: 202-25.
Crossref Google Scholar
3

Sun JC, Lanier LL. NK cell development, homeostasis and function: parallels with CD8(+) T cells. Nat Rev Immunol. 2011; 11: 645-57.
Crossref Google Scholar
4

Zhang Q, Bi J, Zheng X, Chen Y, Wang H, 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.
Crossref Google Scholar
5

Zhang C, Hu Y, Xiao W, Tian Z. Chimeric antigen receptor- and natural killer cell receptor-engineered innate killer cells in cancer immunotherapy. Cell Mol Immunol. 2021; 18: 2083-100.
Crossref Google Scholar
6

Xue W, Zhang M. Updating targets for natural killer/T-cell lymphoma immunotherapy. Cancer Biol Med. 2021; 18: 52-62.
Crossref Google Scholar
7

Xu Z, Huang X. Cellular immunotherapy for hematological malignancy: recent progress and future perspectives. Cancer Biol Med. 2021; 18: 966-80.
Crossref Google Scholar
8

Ruf B, Heinrich B, Greten TF. Immunobiology and immunotherapy of HCC: spotlight on innate and innate-like immune cells. Cell Mol Immunol. 2021; 18: 112-27.
Crossref Google Scholar
9

Fang F, Xie S, Chen M, Li Y, Yue J, Ma J, et al. Advances in NK cell production. Cell Mol Immunol. 2022; 19: 460-81.
Crossref Google Scholar
10

Freud AG, Mundy-Bosse BL, Yu J, Caligiuri MA. The Broad Spectrum of Human Natural Killer Cell Diversity. Immunity. 2017; 47: 820-33.
Crossref Google Scholar
11

Doherty DG, Norris S, Madrigal-Estebas L, McEntee G, Traynor O, 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.
Crossref Google Scholar
12

Doherty DG, O’Farrelly C. Innate and adaptive lymphoid cells in the human liver. Immunol Rev. 2000; 174: 5-20.
Crossref Google Scholar
13

Ahmed O, Robinson MW, O’Farrelly C. Inflammatory processes in the liver: divergent roles in homeostasis and pathology. Cell Mol Immunol. 2021; 18: 1375-86.
Crossref Google Scholar
14

Peng H, Jiang X, Chen Y, Sojka DK, Wei H, Gao X, et al. Liver-resident NK cells confer adaptive immunity in skin-contact inflammation. J Clin Invest. 2013; 123: 1444-56.
Crossref Google Scholar
15

Lunemann S, Martrus G, Goebels H, Kautz T, Langeneckert A, Salzberger W, et al. Hobit expression by a subset of human liver-resident CD56(bright) Natural Killer cells. Sci Rep. 2017; 7: 6676
Crossref Google Scholar
16

Stegmann KA, Robertson F, Hansi N, Gill U, Pallant C, 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.
Crossref Google Scholar
17

Harmon C, Robinson MW, Fahey R, Whelan S, Houlihan DD, 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.
Crossref Google Scholar
18

Aw Yeang HX, Piersma SJ, Lin Y, Yang L, Malkova ON, Miner C, et al. Cutting Edge: Human CD49e- NK Cells Are Tissue Resident in the Liver. J Immunol. 2017; 198: 1417-22.
Crossref Google Scholar
19

Hudspeth K, Donadon M, Cimino M, Pontarini E, Tentorio P, 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.
Crossref Google Scholar
20

Sun Y, Zhou J, Fan J, Yang X. Single-cell RNA sequencing reveals spatial heterogeneity and immune evasion of circulating tumor cells. Cancer Biology & Medicine. 2021; 18: 934-6.
Crossref Google Scholar
21

Wang L, Mo S, Li X, He Y, 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.
Crossref Google Scholar
22

Papalexi E, Satija R. Single-cell RNA sequencing to explore immune cell heterogeneity. Nat Rev Immunol. 2018; 18: 35-45.
Crossref Google Scholar
23

Yang C, Siebert JR, Burns R, Gerbec ZJ, Bonacci B, Rymaszewski A, et al. Heterogeneity of human bone marrow and blood natural killer cells defined by single-cell transcriptome. Nat Commun. 2019; 10: 3931.
Crossref Google Scholar
24

Smith SL, Kennedy PR, Stacey KB, Worboys JD, Yarwood A, Seo S, et al. Diversity of peripheral blood human NK cells identified by single-cell RNA sequencing. Blood Adv. 2020; 4: 1388-406.
Crossref Google Scholar
25

Crinier A, Milpied P, Escaliere B, Piperoglou C, Galluso J, 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.
Crossref Google Scholar
26

Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, 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.
Crossref Google Scholar
27

Sun D, Li H, Cao M, He S, Lei L, Peng J, et al. Cancer burden in China: trends, risk factors and prevention. Cancer Biol Med. 2020; 17: 879-95.
Crossref Google Scholar
28

Villanueva A. Hepatocellular Carcinoma. N Engl J Med. 2019; 380: 1450-62.
Crossref Google Scholar
29

MacParland SA, Liu JC, Ma XZ, Innes BT, Bartczak AM, Gage BK, et al. Single cell RNA sequencing of human liver reveals distinct intrahepatic macrophage populations. Nat Commun. 2018; 9: 4383.
Crossref Google Scholar
30

Zhao J, Zhang S, Liu Y, He X, Qu M, Xu G, et al. Single-cell RNA sequencing reveals the heterogeneity of liver-resident immune cells in human. Cell Discovery. 2020; 6: 22.
Crossref Google Scholar
31

Sun Y, Wu L, Zhong Y, Zhou K, Hou Y, Wang Z, et al. Single-cell landscape of the ecosystem in early-relapse hepatocellular carcinoma. Cell. 2021; 184: 404-21 e16.
Crossref Google Scholar
32

Zhang Q, He Y, Luo N, Patel SJ, Han Y, Gao R, et al. Landscape and Dynamics of Single Immune Cells in Hepatocellular Carcinoma. Cell. 2019; 179: 829-45 e20.
Crossref Google Scholar
33

Stuart T, Butler A, Hoffman P, Hafemeister C, Papalexi E, Mauck WM, 3rd, et al. Comprehensive Integration of Single-Cell Data. Cell. 2019; 177: 1888-902 e21.
Crossref Google Scholar
34

Butler A, Hoffman P, Smibert P, Papalexi E, Satija R. Integrating single-cell transcriptomic data across different conditions, technologies, and species. Nat Biotechnol. 2018; 36: 411-20.
Crossref Google Scholar
35

Mazzurana L, Czarnewski P, Jonsson V, Wigge L, Ringner M, 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.
Crossref Google Scholar
36

Bjorklund AK, Forkel M, Picelli S, Konya V, Theorell J, Friberg D, et al. The heterogeneity of human CD127(+) innate lymphoid cells revealed by single-cell RNA sequencing. Nat Immunol. 2016; 17: 451-60.
Crossref Google Scholar
37

Traag VA, Waltman L, van Eck NJ. From Louvain to Leiden: guaranteeing well-connected communities. Sci Rep. 2019; 9: 5233.
Crossref Google Scholar
38

Haghverdi L, Lun ATL, Morgan MD, Marioni JC. Batch effects in single-cell RNA-sequencing data are corrected by matching mutual nearest neighbors. Nat Biotechnol. 2018; 36: 421-7.
Crossref Google Scholar
39

Scheiter M, Lau U, van Ham M, Bulitta B, Grobe L, Garritsen H, et al. Proteome analysis of distinct developmental stages of human natural killer (NK) cells. Mol Cell Proteomics. 2013; 12: 1099-114.
Crossref Google Scholar
40

Yu J, Mao HC, Wei M, Hughes T, Zhang J, 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.
Crossref Google Scholar
41

Erokhina SA, Streltsova MA, Kanevskiy LM, Grechikhina MV, Sapozhnikov AM, Kovalenko EI. HLA-DR-expressing NK cells: Effective killers suspected for antigen presentation. J Leukoc Biol. 2021; 109: 327-37.
Crossref Google Scholar
42

Erokhina SA, Streltsova MA, Kanevskiy LM, Telford WG, Sapozhnikov AM, Kovalenko EI. HLA-DR(+) NK cells are mostly characterized by less mature phenotype and high functional activity. Immunol Cell Biol. 2018; 96: 212-28.
Crossref Google Scholar
43

Hanna J, Bechtel P, Zhai Y, Youssef F, McLachlan K, Mandelboim O. Novel insights on human NK cells’ immunological modalities revealed by gene expression profiling. J Immunol. 2004; 173: 6547-63.
Crossref Google Scholar
44

Sun H, Liu L, Huang Q, Liu H, Huang M, 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.
Crossref Google Scholar
45

Pan D, Kobayashi A, Jiang P, Ferrari de Andrade L, Tay RE, Luoma AM, et al. A major chromatin regulator determines resistance of tumor cells to T cell-mediated killing. Science. 2018; 359: 770-5.
Crossref Google Scholar
46

Paijens ST, Vledder A, de Bruyn M, Nijman HW. Tumor-infiltrating lymphocytes in the immunotherapy era. Cell Mol Immunol. 2021; 18: 842-59.
Crossref Google Scholar
47

Zhang Y, 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.
Crossref Google Scholar
48

Aizarani N, Saviano A, Sagar X, Mailly L, Durand S, Herman JS, et al. A human liver cell atlas reveals heterogeneity and epithelial progenitors. Nature. 2019; 572: 199-204.
Crossref Google Scholar
49

Wang L, Li J, He S, Liu Y, Chen H, He S, et al. Resolving the graft ischemia-reperfusion injury during liver transplantation at the single cell resolution. Cell Death Dis. 2021; 12: 589.
Crossref Google Scholar
50

Sun C, Xu J, Huang Q, Huang M, Wen H, 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.
Crossref Google Scholar
51

Sun H, Huang Q, Huang M, Wen H, Lin R, 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.
Crossref Google Scholar
52

Yu L, Liu X, Wang X, Yan F, Wang P, 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.
Crossref Google Scholar
53

Jameson G, Robinson MW. Insights Into Human Intrahepatic NK Cell Function From Single Cell RNA Sequencing Datasets. Front Immunol. 2021; 12: 649311.
Crossref Google Scholar
54

Han J, Chen C, Wang C, Qin N, Huang M, Ma Z, et al. Transcriptome-wide association study for persistent hepatitis B virus infection and related hepatocellular carcinoma. Liver Int. 2020; 40: 2117-27.
Crossref Google Scholar
55

Wang XK, Liao XW, Yang CK, Yu TD, Liu ZQ, 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.
Crossref Google Scholar
Cancer Biology & Medicine
Volume 19 Issue 9,
September 2022
Pages 1334-1351
DOI: 10.20892/j.issn.2095-3941.2022.0050
Cite this article:
Liu H, Zhao R, Qin R, et al. Panoramic comparison between NK cells in healthy and cancerous liver through single-cell RNA sequencing. Cancer Biology & Medicine, 2022, 19(9): 1334-1351. https://doi.org/10.20892/j.issn.2095-3941.2022.0050

174

Views

2

Downloads

2

Crossref

6

Web of Science

6

Scopus

Altmetrics
Received: 04 February 2022
Accepted: 15 April 2022
Published: 22 September 2022
©2022 Cancer Biology & Medicine.

Creative Commons Attribution-NonCommercial 4.0 International License
Return