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Semin Liver Dis 2024; 44(02): 133-146
DOI: 10.1055/s-0044-1787152
Review Article

Heterogeneity in Liver Cancer Immune Microenvironment: Emerging Single-Cell and Spatial Perspectives

Caiyi Cherry Li   *
1   Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
,
Meng Liu   *
1   Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
,
Hsin-Pei Lee
1   Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
,
Wenqi Wu
1   Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
,
Lichun Ma
1   Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
2   Liver Cancer Program, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
› Institutsangaben Funding This work was supported by grants (ZIA BC 012079 and ZIA BC 012083) from the intramural research program of the Center for Cancer Research, National Cancer Institute of the United States.
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Abstract

Primary liver cancer is a solid malignancy with a high mortality rate. The success of immunotherapy has shown great promise in improving patient care and highlights a crucial need to understand the complexity of the liver tumor immune microenvironment (TIME). Recent advances in single-cell and spatial omics technologies, coupled with the development of systems biology approaches, are rapidly transforming the landscape of tumor immunology. Here we review the cellular landscape of liver TIME from single-cell and spatial perspectives. We also discuss the cellular interaction networks within the tumor cell community in regulating immune responses. We further highlight the challenges and opportunities with implications for biomarker discovery, patient stratification, and combination immunotherapies.

Keywords

liver cancer - tumor immune microenvironment - immunotherapy - single cell and spatial omics - tumor heterogeneity

Authors' Contributions

L.M. developed study concept; C.C.L., M.L., H-P.L., W.W., and L.M. wrote the manuscript. All authors read, edited, and approved the manuscript.


* Contributed equally to this manuscript.




Publikationsverlauf

Artikel online veröffentlicht:
24. Mai 2024

© 2024. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
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  • References

  • 1 Llovet JM, Kelley RK, Villanueva A. et al. Hepatocellular carcinoma. Nat Rev Dis Primers 2021; 7 (01) 6
    CrossrefPubMedGoogle Scholar
  • 2 Loeuillard E, Conboy CB, Gores GJ, Rizvi S. Immunobiology of cholangiocarcinoma. JHEP Rep Innov Hepatol 2019; 1 (04) 297-311
    CrossrefPubMedGoogle Scholar
  • 3 Tabrizian P, Jibara G, Shrager B, Schwartz M, Roayaie S. Recurrence of hepatocellular cancer after resection: patterns, treatments, and prognosis. Ann Surg 2015; 261 (05) 947-955
    CrossrefPubMedGoogle Scholar
  • 4 Greten TF, Sangro B. Targets for immunotherapy of liver cancer. J Hepatol 2017 DOI: 10.1016/j.jhep.2017.09.007
    CrossrefPubMedGoogle Scholar
  • 5 Martin SP, Wang XW. The evolving landscape of precision medicine in primary liver cancer. Hepat Oncol 2019; 6 (02) HEP12
    CrossrefPubMedGoogle Scholar
  • 6 Sangro B, Sarobe P, Hervás-Stubbs S, Melero I. Advances in immunotherapy for hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 2021; 18 (08) 525-543
    CrossrefPubMedGoogle Scholar
  • 7 Cheng AL, Qin S, Ikeda M. et al. Updated efficacy and safety data from IMbrave150: atezolizumab plus bevacizumab vs. sorafenib for unresectable hepatocellular carcinoma. J Hepatol 2022; 76 (04) 862-873
    CrossrefPubMedGoogle Scholar
  • 8 Greten TF, Villanueva A, Korangy F. et al. Biomarkers for immunotherapy of hepatocellular carcinoma. Nat Rev Clin Oncol 2023; 20 (11) 780-798
    CrossrefPubMedGoogle Scholar
  • 9 Binnewies M, Roberts EW, Kersten K. et al. Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat Med 2018; 24 (05) 541-550
    CrossrefPubMedGoogle Scholar
  • 10 Budhu A, Pehrsson EC, He A. et al. Tumor biology and immune infiltration define primary liver cancer subsets linked to overall survival after immunotherapy. Cell Rep Med 2023; 4 (06) 101052
    CrossrefPubMedGoogle Scholar
  • 11 Racanelli V, Rehermann B. The liver as an immunological organ. Hepatology 2006; 43 (2, Suppl 1): S54-S62
    CrossrefPubMedGoogle Scholar
  • 12 MacParland SA, Liu JC, Ma XZ. et al. Single cell RNA sequencing of human liver reveals distinct intrahepatic macrophage populations. Nat Commun 2018; 9 (01) 4383
    CrossrefPubMedGoogle Scholar
  • 13 Kurioka A, Walker LJ, Klenerman P, Willberg CB. MAIT cells: new guardians of the liver. Clin Transl Immunology 2016; 5 (08) e98
    CrossrefPubMedGoogle Scholar
  • 14 Giraud J, Chalopin D, Blanc JF, Saleh M. Hepatocellular carcinoma immune landscape and the potential of immunotherapies. Front Immunol 2021; 12: 655697
    CrossrefPubMedGoogle Scholar
  • 15 Li X, Ramadori P, Pfister D, Seehawer M, Zender L, Heikenwalder M. The immunological and metabolic landscape in primary and metastatic liver cancer. Nat Rev Cancer 2021; 21 (09) 541-557
    CrossrefPubMedGoogle Scholar
  • 16 Thorsson V, Gibbs DL, Brown SD. et al; Cancer Genome Atlas Research Network. The immune landscape of cancer. Immunity 2018; 48 (04) 812-830.e14
    CrossrefPubMedGoogle Scholar
  • 17 Barkley D, Moncada R, Pour M. et al. Cancer cell states recur across tumor types and form specific interactions with the tumor microenvironment. Nat Genet 2022; 54 (08) 1192-1201
    CrossrefPubMedGoogle Scholar
  • 18 Christo SN, Evrard M, Park SL. et al. Discrete tissue microenvironments instruct diversity in resident memory T cell function and plasticity. Nat Immunol 2021; 22 (09) 1140-1151
    CrossrefPubMedGoogle Scholar
  • 19 Ma L, Hernandez MO, Zhao Y. et al. Tumor cell biodiversity drives microenvironmental reprogramming in liver cancer. Cancer Cell 2019; 36 (04) 418-430.e6
    CrossrefPubMedGoogle Scholar
  • 20 Mempel TR, Lill JK, Altenburger LM. How chemokines organize the tumour microenvironment. Nat Rev Cancer 2024; 24 (01) 28-50
    CrossrefPubMedGoogle Scholar
  • 21 Yang F, Hilakivi-Clarke L, Shaha A. et al. Metabolic reprogramming and its clinical implication for liver cancer. Hepatology 2023; 78 (05) 1602-1624
    CrossrefPubMedGoogle Scholar
  • 22 Liu J, Dang H, Wang XW. The significance of intertumor and intratumor heterogeneity in liver cancer. Exp Mol Med 2018; 50 (01) e416
    CrossrefPubMedGoogle Scholar
  • 23 Pfister D, Núñez NG, Pinyol R. et al. NASH limits anti-tumour surveillance in immunotherapy-treated HCC. Nature 2021; 592 (7854) 450-456
    CrossrefPubMedGoogle Scholar
  • 24 de Visser KE, Joyce JA. The evolving tumor microenvironment: from cancer initiation to metastatic outgrowth. Cancer Cell 2023; 41 (03) 374-403
    CrossrefPubMedGoogle Scholar
  • 25 van Vlerken-Ysla L, Tyurina YY, Kagan VE, Gabrilovich DI. Functional states of myeloid cells in cancer. Cancer Cell 2023; 41 (03) 490-504
    CrossrefPubMedGoogle Scholar
  • 26 Dolina JS, Van Braeckel-Budimir N, Thomas GD, Salek-Ardakani S. CD8+ T cell exhaustion in cancer. Front Immunol 2021; 12: 715234
    CrossrefPubMedGoogle Scholar
  • 27 Sharma P, Siddiqui BA, Anandhan S. et al. The next decade of immune checkpoint therapy. Cancer Discov 2021; 11 (04) 838-857
    CrossrefPubMedGoogle Scholar
  • 28 Zhang N, Bevan MJ. CD8(+) T cells: foot soldiers of the immune system. Immunity 2011; 35 (02) 161-168
    CrossrefPubMedGoogle Scholar
  • 29 Speiser DE, Chijioke O, Schaeuble K, Münz C. CD4+ T cells in cancer. Nat Cancer 2023; 4 (03) 317-329
    CrossrefPubMedGoogle Scholar
  • 30 St Paul M, Ohashi PS. The roles of CD8+ T cell subsets in antitumor immunity. Trends Cell Biol 2020; 30 (09) 695-704
    CrossrefPubMedGoogle Scholar
  • 31 Duan M, Goswami S, Shi JY. et al. Activated and exhausted MAIT cells foster disease progression and indicate poor outcome in hepatocellular carcinoma. Clin Cancer Res 2019; 25 (11) 3304-3316
    CrossrefPubMedGoogle Scholar
  • 32 Kotsari M, Dimopoulou V, Koskinas J, Armakolas A. Immune system and hepatocellular carcinoma (HCC): new insights into HCC progression. Int J Mol Sci 2023; 24 (14) 24
    CrossrefPubMedGoogle Scholar
  • 33 Doherty DG, O'Farrelly C. Innate and adaptive lymphoid cells in the human liver. Immunol Rev 2000; 174: 5-20
    CrossrefPubMedGoogle Scholar
  • 34 Ruf B, Bruhns M, Babaei S. et al. Tumor-associated macrophages trigger MAIT cell dysfunction at the HCC invasive margin. Cell 2023; 186 (17) 3686-3705.e32
    CrossrefPubMedGoogle Scholar
  • 35 Zhao N, Dang H, Ma L. et al. Intratumoral γδ T-cell infiltrates, chemokine (C-C motif) ligand 4/chemokine (C-C motif) ligand 5 protein expression and survival in patients with hepatocellular carcinoma. Hepatology 2021; 73 (03) 1045-1060
    CrossrefPubMedGoogle Scholar
  • 36 He W, Hu Y, Chen D. et al. Hepatocellular carcinoma-infiltrating γδ T cells are functionally defected and allogenic Vδ2+ γδ T cell can be a promising complement. Clin Transl Med 2022; 12 (04) e800
    CrossrefPubMedGoogle Scholar
  • 37 Chandwaskar R, Awasthi A. Emerging roles of Th9 cells as an anti-tumor helper T cells. Int Rev Immunol 2019; 38 (05) 204-211
    CrossrefPubMedGoogle Scholar
  • 38 Bian J, Lin J, Long J. et al. T lymphocytes in hepatocellular carcinoma immune microenvironment: insights into human immunology and immunotherapy. Am J Cancer Res 2020; 10 (12) 4585-4606
    PubMedGoogle Scholar
  • 39 Chen X, Du Y, Hu Q, Huang Z. Tumor-derived CD4+CD25+regulatory T cells inhibit dendritic cells function by CTLA-4. Pathol Res Pract 2017; 213 (03) 245-249
    CrossrefPubMedGoogle Scholar
  • 40 Ono M. Control of regulatory T-cell differentiation and function by T-cell receptor signalling and Foxp3 transcription factor complexes. Immunology 2020; 160 (01) 24-37
    CrossrefPubMedGoogle Scholar
  • 41 Tan H, Wang S, Zhao L. A tumour-promoting role of Th9 cells in hepatocellular carcinoma through CCL20 and STAT3 pathways. Clin Exp Pharmacol Physiol 2017; 44 (02) 213-221
    CrossrefPubMedGoogle Scholar
  • 42 Lee HL, Jang JW, Lee SW. et al. Inflammatory cytokines and change of Th1/Th2 balance as prognostic indicators for hepatocellular carcinoma in patients treated with transarterial chemoembolization. Sci Rep 2019; 9 (01) 3260
    CrossrefPubMedGoogle Scholar
  • 43 Budhu A, Forgues M, Ye QH. et al. Prediction of venous metastases, recurrence, and prognosis in hepatocellular carcinoma based on a unique immune response signature of the liver microenvironment. Cancer Cell 2006; 10 (02) 99-111
    CrossrefPubMedGoogle Scholar
  • 44 Zhang JP, Yan J, Xu J. et al. Increased intratumoral IL-17-producing cells correlate with poor survival in hepatocellular carcinoma patients. J Hepatol 2009; 50 (05) 980-989
    CrossrefPubMedGoogle Scholar
  • 45 Murugaiyan G, Saha B. Protumor vs antitumor functions of IL-17. J Immunol 2009; 183 (07) 4169-4175
    CrossrefPubMedGoogle Scholar
  • 46 Qin S, Ma S, Huang X, Lu D, Zhou Y, Jiang H. Th22 cells are associated with hepatocellular carcinoma development and progression. Chin J Cancer Res 2014; 26 (02) 135-141
    PubMedGoogle Scholar
  • 47 Zhang J, Liu Z, Liu L, Huang M, Huang Y. Th22/IL-22 mediates the progression of HBV-related hepatocellular carcinoma via STAT3. Cytotechnology 2022; 74 (02) 203-216
    CrossrefPubMedGoogle Scholar
  • 48 Duhen T, Duhen R, Lanzavecchia A, Sallusto F, Campbell DJ. Functionally distinct subsets of human FOXP3+ Treg cells that phenotypically mirror effector Th cells. Blood 2012; 119 (19) 4430-4440
    CrossrefPubMedGoogle Scholar
  • 49 Bhairavabhotla R, Kim YC, Glass DD. et al. Transcriptome profiling of human FoxP3+ regulatory T cells. Hum Immunol 2016; 77 (02) 201-213
    CrossrefPubMedGoogle Scholar
  • 50 Zheng C, Zheng L, Yoo JK. et al. Landscape of infiltrating T cells in liver cancer revealed by single-cell sequencing. Cell 2017; 169 (07) 1342-1356.e16
    CrossrefPubMedGoogle Scholar
  • 51 Mittermüller D, Otto L, Long Z. et al. Regulatory T cells suppress the motility of cytotoxic T cells in friend retrovirus-infected mice. JCI Insight 2023; 8 (13) 8
    CrossrefPubMedGoogle Scholar
  • 52 Chauhan P, Hu S, Sheng WS, Lokensgard JR. Regulatory T-cells suppress cytotoxic T lymphocyte responses against microglia. Cells 2022; 11 (18) 11
    CrossrefPubMedGoogle Scholar
  • 53 Fu J, Xu D, Liu Z. et al. Increased regulatory T cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients. Gastroenterology 2007; 132 (07) 2328-2339
    CrossrefPubMedGoogle Scholar
  • 54 Yang Y, Liu F, Liu W. et al. Analysis of single-cell RNAseq identifies transitional states of T cells associated with hepatocellular carcinoma. Clin Transl Med 2020; 10 (03) e133
    CrossrefPubMedGoogle Scholar
  • 55 Chaoul N, Mancarella S, Lupo L, Giannelli G, Dituri F. Impaired anti-tumor T cell response in hepatocellular carcinoma. Cancers (Basel) 2020; 12 (03) 12
    CrossrefPubMedGoogle Scholar
  • 56 Böttcher JP, Beyer M, Meissner F. et al. Functional classification of memory CD8(+) T cells by CX3CR1 expression. Nat Commun 2015; 6: 8306
    CrossrefPubMedGoogle Scholar
  • 57 Xue R, Zhang Q, Cao Q. et al. Liver tumour immune microenvironment subtypes and neutrophil heterogeneity. Nature 2022; 612 (7938) 141-147
    CrossrefPubMedGoogle Scholar
  • 58 Schietinger A, Philip M, Krisnawan VE. et al. Tumor-specific T cell dysfunction is a dynamic antigen-driven differentiation program initiated early during tumorigenesis. Immunity 2016; 45 (02) 389-401
    CrossrefPubMedGoogle Scholar
  • 59 Khan O, Giles JR, McDonald S. et al. TOX transcriptionally and epigenetically programs CD8+ T cell exhaustion. Nature 2019; 571 (7764) 211-218
    CrossrefPubMedGoogle Scholar
  • 60 Chen L, Han X. Anti-PD-1/PD-L1 therapy of human cancer: past, present, and future. J Clin Invest 2015; 125 (09) 3384-3391
    CrossrefPubMedGoogle Scholar
  • 61 Budimir N, Thomas GD, Dolina JS, Salek-Ardakani S. Reversing T-cell exhaustion in cancer: lessons learned from PD-1/PD-L1 immune checkpoint blockade. Cancer Immunol Res 2022; 10 (02) 146-153
    CrossrefPubMedGoogle Scholar
  • 62 Zheng L, Qin S, Si W. et al. Pan-cancer single-cell landscape of tumor-infiltrating T cells. Science 2021; 374 (6574) abe6474
    CrossrefPubMedGoogle Scholar
  • 63 Barsch M, Salié H, Schlaak AE. et al. T-cell exhaustion and residency dynamics inform clinical outcomes in hepatocellular carcinoma. J Hepatol 2022; 77 (02) 397-409
    CrossrefPubMedGoogle Scholar
  • 64 Ma L, Wang L, Khatib SA. et al. Single-cell atlas of tumor cell evolution in response to therapy in hepatocellular carcinoma and intrahepatic cholangiocarcinoma. J Hepatol 2021; 75 (06) 1397-1408
    CrossrefPubMedGoogle Scholar
  • 65 Cappuyns S, Philips G, Vandecaveye V. et al. PD-1- CD45RA+ effector-memory CD8 T cells and CXCL10+ macrophages are associated with response to atezolizumab plus bevacizumab in advanced hepatocellular carcinoma. Nat Commun 2023; 14 (01) 7825
    CrossrefPubMedGoogle Scholar
  • 66 Magen A, Hamon P, Fiaschi N. et al. Intratumoral dendritic cell-CD4+ T helper cell niches enable CD8+ T cell differentiation following PD-1 blockade in hepatocellular carcinoma. Nat Med 2023; 29 (06) 1389-1399
    CrossrefPubMedGoogle Scholar
  • 67 Laumont CM, Nelson BH. B cells in the tumor microenvironment: multi-faceted organizers, regulators, and effectors of anti-tumor immunity. Cancer Cell 2023; 41 (03) 466-489
    CrossrefPubMedGoogle Scholar
  • 68 Kurosaki T, Kometani K, Ise W. Memory B cells. Nat Rev Immunol 2015; 15 (03) 149-159
    CrossrefPubMedGoogle Scholar
  • 69 Kinker GS, Vitiello GAF, Ferreira WAS, Chaves AS, Cordeiro de Lima VC, Medina TDS. B cell orchestration of anti-tumor immune responses: a matter of cell localization and communication. Front Cell Dev Biol 2021; 9: 678127
    CrossrefPubMedGoogle Scholar
  • 70 Morgan D, Tergaonkar V. Unraveling B cell trajectories at single cell resolution. Trends Immunol 2022; 43 (03) 210-229
    CrossrefPubMedGoogle Scholar
  • 71 Zhang Z, Ma L, Goswami S. et al. Landscape of infiltrating B cells and their clinical significance in human hepatocellular carcinoma. OncoImmunology 2019; 8 (04) e1571388
    CrossrefPubMedGoogle Scholar
  • 72 Garnelo M, Tan A, Her Z. et al. Interaction between tumour-infiltrating B cells and T cells controls the progression of hepatocellular carcinoma. Gut 2017; 66 (02) 342-351
    CrossrefPubMedGoogle Scholar
  • 73 Zhang S, Liu Z, Wu D, Chen L, Xie L. Single-cell RNA-Seq analysis reveals microenvironmental infiltration of plasma cells and hepatocytic prognostic markers in HCC with cirrhosis. Front Oncol 2020; 10: 596318
    CrossrefPubMedGoogle Scholar
  • 74 Xu Y, Wei Z, Feng M. et al. Tumor-infiltrated activated B cells suppress liver metastasis of colorectal cancers. Cell Rep 2022; 40 (09) 111295
    CrossrefPubMedGoogle Scholar
  • 75 Zhang S, Yuan L, Danilova L. et al. Spatial transcriptomics analysis of neoadjuvant cabozantinib and nivolumab in advanced hepatocellular carcinoma identifies independent mechanisms of resistance and recurrence. Genome Med 2023; 15 (01) 72
    CrossrefPubMedGoogle Scholar
  • 76 Helmink BA, Reddy SM, Gao J. et al. B cells and tertiary lymphoid structures promote immunotherapy response. Nature 2020; 577 (7791) 549-555
    CrossrefPubMedGoogle Scholar
  • 77 Ma L, Heinrich S, Wang L. et al. Multiregional single-cell dissection of tumor and immune cells reveals stable lock-and-key features in liver cancer. Nat Commun 2022; 13 (01) 7533
    CrossrefPubMedGoogle Scholar
  • 78 Mi H, Ho WJ, Yarchoan M, Popel AS. Multi-scale spatial analysis of the tumor microenvironment reveals features of cabozantinib and nivolumab efficacy in hepatocellular carcinoma. Front Immunol 2022; 13: 892250
    CrossrefPubMedGoogle Scholar
  • 79 Sharma A, Seow JJW, Dutertre CA. et al. Onco-fetal reprogramming of endothelial cells drives immunosuppressive macrophages in hepatocellular carcinoma. Cell 2020; 183 (02) 377-394.e21
    CrossrefPubMedGoogle Scholar
  • 80 Zhang M, Yang H, Wan L. et al. Single-cell transcriptomic architecture and intercellular crosstalk of human intrahepatic cholangiocarcinoma. J Hepatol 2020; 73 (05) 1118-1130
    CrossrefPubMedGoogle Scholar
  • 81 Zheng H, Peng X, Yang S. et al. Targeting tumor-associated macrophages in hepatocellular carcinoma: biology, strategy, and immunotherapy. Cell Death Discov 2023; 9 (01) 65
    CrossrefPubMedGoogle Scholar
  • 82 Arvanitakis K, Koletsa T, Mitroulis I, Germanidis G. Tumor-associated macrophages in hepatocellular carcinoma pathogenesis, prognosis and therapy. Cancers (Basel) 2022; 14 (01) 14
    CrossrefPubMedGoogle Scholar
  • 83 Yang L, Zhang Y. Tumor-associated macrophages: from basic research to clinical application. J Hematol Oncol 2017; 10 (01) 58
    CrossrefPubMedGoogle Scholar
  • 84 Zhang YL, Li Q, Yang XM. et al. SPON2 promotes M1-like macrophage recruitment and inhibits hepatocellular carcinoma metastasis by distinct integrin-rho GTPase-Hippo pathways. Cancer Res 2018; 78 (09) 2305-2317
    CrossrefPubMedGoogle Scholar
  • 85 Wang YF, Yuan SX, Jiang H. et al. Spatial maps of hepatocellular carcinoma transcriptomes reveal spatial expression patterns in tumor immune microenvironment. Theranostics 2022; 12 (09) 4163-4180
    CrossrefPubMedGoogle Scholar
  • 86 Song G, Shi Y, Zhang M. et al. Global immune characterization of HBV/HCV-related hepatocellular carcinoma identifies macrophage and T-cell subsets associated with disease progression. Cell Discov 2020; 6 (01) 90
    CrossrefPubMedGoogle Scholar
  • 87 Ma RY, Black A, Qian BZ. Macrophage diversity in cancer revisited in the era of single-cell omics. Trends Immunol 2022; 43 (07) 546-563
    CrossrefPubMedGoogle Scholar
  • 88 Liu Y, Xun Z, Ma K. et al. Identification of a tumour immune barrier in the HCC microenvironment that determines the efficacy of immunotherapy. J Hepatol 2023; 78 (04) 770-782
    CrossrefPubMedGoogle Scholar
  • 89 Xun Z, Ding X, Zhang Y. et al. Reconstruction of the tumor spatial microenvironment along the malignant-boundary-nonmalignant axis. Nat Commun 2023; 14 (01) 933
    CrossrefPubMedGoogle Scholar
  • 90 Zhang Q, He Y, Luo N. et al. Landscape and dynamics of single immune cells in hepatocellular carcinoma. Cell 2019; 179 (04) 829-845.e20
    CrossrefPubMedGoogle Scholar
  • 91 Li Z, Pai R, Gupta S. et al. Presence of onco-fetal neighborhoods in hepatocellular carcinoma is associated with relapse and response to immunotherapy. Nat Cancer 2024; 5 (01) 167-186
    CrossrefPubMedGoogle Scholar
  • 92 Duan Z, Luo Y. Targeting macrophages in cancer immunotherapy. Signal Transduct Target Ther 2021; 6 (01) 127
    CrossrefPubMedGoogle Scholar
  • 93 Wang Q, Lin Y, Yu W, Chen X, He Q, Ye Z. The core role of macrophages in hepatocellular carcinoma: the definition of molecular subtypes and the prognostic risk system. Front Pharmacol 2023; 14: 1228052
    CrossrefPubMedGoogle Scholar
  • 94 Geh D, Leslie J, Rumney R, Reeves HL, Bird TG, Mann DA. Neutrophils as potential therapeutic targets in hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 2022; 19 (04) 257-273
    CrossrefPubMedGoogle Scholar
  • 95 Fridlender ZG, Sun J, Kim S. et al. Polarization of tumor-associated neutrophil phenotype by TGF-beta: “N1” versus “N2” TAN. Cancer Cell 2009; 16 (03) 183-194
    CrossrefPubMedGoogle Scholar
  • 96 Grieshaber-Bouyer R, Radtke FA, Cunin P. et al; ImmGen Consortium. The neutrotime transcriptional signature defines a single continuum of neutrophils across biological compartments. Nat Commun 2021; 12 (01) 2856
    CrossrefPubMedGoogle Scholar
  • 97 Meng Y, Ye F, Nie P. et al. Immunosuppressive CD10+ALPL+ neutrophils promote resistance to anti-PD-1 therapy in HCC by mediating irreversible exhaustion of T cells. J Hepatol 2023; 79 (06) 1435-1449
    CrossrefPubMedGoogle Scholar
  • 98 Bald T, Krummel MF, Smyth MJ, Barry KC. The NK cell-cancer cycle: advances and new challenges in NK cell-based immunotherapies. Nat Immunol 2020; 21 (08) 835-847
    CrossrefPubMedGoogle Scholar
  • 99 Mikulak J, Bruni E, Oriolo F, Di Vito C, Mavilio D. Hepatic natural killer cells: organ-specific sentinels of liver immune homeostasis and physiopathology. Front Immunol 2019; 10: 946
    CrossrefPubMedGoogle Scholar
  • 100 Freud AG, Mundy-Bosse BL, Yu J, Caligiuri MA. The broad spectrum of human natural killer cell diversity. Immunity 2017; 47 (05) 820-833
    CrossrefPubMedGoogle Scholar
  • 101 Stegmann KA, Robertson F, Hansi N. 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
    CrossrefPubMedGoogle Scholar
  • 102 Hudspeth K, Donadon M, Cimino 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
    CrossrefPubMedGoogle Scholar
  • 103 Zhao J, Zhang S, Liu Y. et al. Single-cell RNA sequencing reveals the heterogeneity of liver-resident immune cells in human. Cell Discov 2020; 6: 22
    CrossrefPubMedGoogle Scholar
  • 104 Wu M, Mei F, Liu W, Jiang J. Comprehensive characterization of tumor infiltrating natural killer cells and clinical significance in hepatocellular carcinoma based on gene expression profiles. Biomed Pharmacother 2020; 121: 109637
    CrossrefPubMedGoogle Scholar
  • 105 Ho DW, Tsui YM, Chan LK. et al. Single-cell RNA sequencing shows the immunosuppressive landscape and tumor heterogeneity of HBV-associated hepatocellular carcinoma. Nat Commun 2021; 12 (01) 3684
    CrossrefPubMedGoogle Scholar
  • 106 Tang F, Li J, Qi L. et al. A pan-cancer single-cell panorama of human natural killer cells. Cell 2023; 186 (19) 4235-4251.e20
    CrossrefPubMedGoogle Scholar
  • 107 Morita S, Kikuchi H, Birch G. et al. Preventing NK cell activation in the damaged liver induced by cabozantinib/PD-1 blockade increases survival in hepatocellular carcinoma models. bioRxiv 2023 DOI: 10.1101/2023.10.20.563378
    CrossrefPubMedGoogle Scholar
  • 108 Patente TA, Pinho MP, Oliveira AA, Evangelista GCM, Bergami-Santos PC, Barbuto JAM. Human dendritic cells: their heterogeneity and clinical application potential in cancer immunotherapy. Front Immunol 2019; 9: 3176
    CrossrefPubMedGoogle Scholar
  • 109 Del Prete A, Salvi V, Soriani A. et al. Dendritic cell subsets in cancer immunity and tumor antigen sensing. Cell Mol Immunol 2023; 20 (05) 432-447
    CrossrefPubMedGoogle Scholar
  • 110 Guilliams M, Dutertre CA, Scott CL. et al. Unsupervised high-dimensional analysis aligns dendritic cells across tissues and species. Immunity 2016; 45 (03) 669-684
    CrossrefPubMedGoogle Scholar
  • 111 Villar J, Segura E. Decoding the heterogeneity of human dendritic cell subsets. Trends Immunol 2020; 41 (12) 1062-1071
    CrossrefPubMedGoogle Scholar
  • 112 Zhu C, Ma J, Zhu K. et al. Spatial immunophenotypes predict clinical outcome in intrahepatic cholangiocarcinoma. JHEP Rep Innov Hepatol 2023; 5 (08) 100762
    CrossrefPubMedGoogle Scholar
  • 113 Bronte V, Brandau S, Chen SH. et al. Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat Commun 2016; 7: 12150
    CrossrefPubMedGoogle Scholar
  • 114 Lasser SA, Ozbay Kurt FG, Arkhypov I, Utikal J, Umansky V. Myeloid-derived suppressor cells in cancer and cancer therapy. Nat Rev Clin Oncol 2024; 21 (02) 147-164
    CrossrefPubMedGoogle Scholar
  • 115 Yang S, Jia J, Wang F. et al. Targeting neutrophils: mechanism and advances in cancer therapy. Clin Transl Med 2024; 14 (03) e1599
    CrossrefPubMedGoogle Scholar
  • 116 Ma T, Renz BW, Ilmer M. et al. Myeloid-derived suppressor cells in solid tumors. Cells 2022; 11 (02) 11
    CrossrefPubMedGoogle Scholar
  • 117 Arihara F, Mizukoshi E, Kitahara M. et al. Increase in CD14+HLA-DR -/low myeloid-derived suppressor cells in hepatocellular carcinoma patients and its impact on prognosis. Cancer Immunol Immunother 2013; 62 (08) 1421-1430
    CrossrefPubMedGoogle Scholar
  • 118 Massalha H, Bahar Halpern K, Abu-Gazala S. et al. A single cell atlas of the human liver tumor microenvironment. Mol Syst Biol 2020; 16 (12) e9682
    CrossrefPubMedGoogle Scholar
  • 119 Fujita M, Yamaguchi R, Hasegawa T. et al. Classification of primary liver cancer with immunosuppression mechanisms and correlation with genomic alterations. EBioMedicine 2020; 53: 102659
    CrossrefPubMedGoogle Scholar
  • 120 Martin-Serrano MA, Kepecs B, Torres-Martin M. et al. Novel microenvironment-based classification of intrahepatic cholangiocarcinoma with therapeutic implications. Gut 2023; 72 (04) 736-748
    CrossrefPubMedGoogle Scholar
  • 121 Lin J, Dai Y, Sang C. et al. Multimodule characterization of immune subgroups in intrahepatic cholangiocarcinoma reveals distinct therapeutic vulnerabilities. J Immunother Cancer 2022; 10 (07) 10
    PubMedGoogle Scholar
  • 122 Zappasodi R, Merghoub T, Wolchok JD. Emerging concepts for immune checkpoint blockade-based combination therapies. Cancer Cell 2018; 33 (04) 581-598
    CrossrefPubMedGoogle Scholar
  • 123 Job S, Rapoud D, Dos Santos A. et al. Identification of four immune subtypes characterized by distinct composition and functions of tumor microenvironment in intrahepatic cholangiocarcinoma. Hepatology 2020; 72 (03) 965-981
    CrossrefPubMedGoogle Scholar
  • 124 Kurebayashi Y, Ojima H, Tsujikawa H. et al. Landscape of immune microenvironment in hepatocellular carcinoma and its additional impact on histological and molecular classification. Hepatology 2018; 68 (03) 1025-1041
    CrossrefPubMedGoogle Scholar
  • 125 Bagaev A, Kotlov N, Nomie K. et al. Conserved pan-cancer microenvironment subtypes predict response to immunotherapy. Cancer Cell 2021; 39 (06) 845-865.e7
    CrossrefPubMedGoogle Scholar
  • 126 Zhang Q, Lou Y, Yang J. et al. Integrated multiomic analysis reveals comprehensive tumour heterogeneity and novel immunophenotypic classification in hepatocellular carcinomas. Gut 2019; 68 (11) 2019-2031
    CrossrefPubMedGoogle Scholar
  • 127 Montironi C, Castet F, Haber PK. et al. Inflamed and non-inflamed classes of HCC: a revised immunogenomic classification. Gut 2023; 72 (01) 129-140
    CrossrefPubMedGoogle Scholar
  • 128 Zhang H, Yao Y, Wu J. et al. Comprehensive analysis identifies and validates the tumor microenvironment subtypes to predict anti-tumor therapy efficacy in hepatocellular carcinoma. Front Immunol 2022; 13: 838374
    CrossrefPubMedGoogle Scholar
  • 129 Maestri E, Kedei N, Khatib S. et al. Spatial proximity of tumor-immune interactions predicts patient outcome in hepatocellular carcinoma. Hepatology 2024; 79 (04) 768-779
    CrossrefPubMedGoogle Scholar
  • 130 Revsine M, Wang L, Forgues M. et al. Lineage and ecology define liver tumor evolution in response to treatment. Cell Rep Med 2024; 5 (02) 101394
    CrossrefPubMedGoogle Scholar
  • 131 Moffitt JR, Lundberg E, Heyn H. The emerging landscape of spatial profiling technologies. Nat Rev Genet 2022; 23 (12) 741-759
    CrossrefPubMedGoogle Scholar
  • 132 Biancalani T, Scalia G, Buffoni L. et al. Deep learning and alignment of spatially resolved single-cell transcriptomes with Tangram. Nat Methods 2021; 18 (11) 1352-1362
    CrossrefPubMedGoogle Scholar
  • 133 Abdelaal T, Mourragui S, Mahfouz A, Reinders MJT. SpaGE: spatial gene enhancement using scRNA-seq. Nucleic Acids Res 2020; 48 (18) e107-e107
    CrossrefPubMedGoogle Scholar
  • 134 Wan X, Xiao J, Tam SST. et al. Integrating spatial and single-cell transcriptomics data using deep generative models with SpatialScope. Nat Commun 2023; 14 (01) 7848
    CrossrefPubMedGoogle Scholar
  • 135 Kirschenbaum D, Xie K, Ingelfinger F. et al. Time-resolved single-cell transcriptomics defines immune trajectories in glioblastoma. Cell 2024; 187 (01) 149-165.e23
    CrossrefPubMedGoogle Scholar
  • 136 Levrero M, Zucman-Rossi J. Mechanisms of HBV-induced hepatocellular carcinoma. J Hepatol 2016; 64 (01) S84-S101
    CrossrefPubMedGoogle Scholar
  • 137 Goto K, Roca Suarez AA, Wrensch F, Baumert TF, Lupberger J. Hepatitis C virus and hepatocellular carcinoma: when the host loses its grip. Int J Mol Sci 2020; 21 (09) 21
    CrossrefPubMedGoogle Scholar
  • 138 Mackowiak B, Fu Y, Maccioni L, Gao B. Alcohol-associated liver disease. J Clin Invest 2024; 134 (03) 134
    CrossrefPubMedGoogle Scholar
  • 139 Parthasarathy G, Revelo X, Malhi H. Pathogenesis of nonalcoholic steatohepatitis: an overview. Hepatol Commun 2020; 4 (04) 478-492
    CrossrefPubMedGoogle Scholar
  • 140 Zheng Q, Sun Q, Yao H. et al. Single-cell landscape identifies the immunophenotypes and microenvironments of HBV-positive and HBV-negative liver cancer. Hepatol Commun 2024; 8 (02) 8
    CrossrefPubMedGoogle Scholar
  • 141 Li M, Wang L, Cong L. et al. Spatial proteomics of immune microenvironment in nonalcoholic steatohepatitis-associated hepatocellular carcinoma. Hepatology 2023;•••
    PubMedGoogle Scholar
  • 142 Mestas J, Hughes CC. Of mice and not men: differences between mouse and human immunology. J Immunol 2004; 172 (05) 2731-2738
    CrossrefPubMedGoogle Scholar
  • 143 Brown ZJ, Heinrich B, Greten TF. Mouse models of hepatocellular carcinoma: an overview and highlights for immunotherapy research. Nat Rev Gastroenterol Hepatol 2018; 15 (09) 536-554
    CrossrefPubMedGoogle Scholar
  • 144 Jeon SH, Lee YJ, Kim HD. et al. Dynamic changes in peripheral blood monocytes early after anti-PD-1 therapy predict clinical outcomes in hepatocellular carcinoma. Cancer Immunol Immunother 2023; 72 (02) 371-384
    CrossrefPubMedGoogle Scholar
  • 145 Kim HD, Jung S, Lim HY. et al. Regorafenib plus nivolumab in unresectable hepatocellular carcinoma: the phase 2 RENOBATE trial. Nat Med 2024; 30 (03) 699-707
    CrossrefPubMedGoogle Scholar
  • 146 Simoni Y, Becht E, Fehlings M. et al. Bystander CD8+ T cells are abundant and phenotypically distinct in human tumour infiltrates. Nature 2018; 557 (7706) 575-579
    CrossrefPubMedGoogle Scholar
  • 147 Liu L, Liu J, Li P. et al. Single-cell analysis reveals HBV-specific PD-1+CD8+ TRM cells in tumor borders are associated with HBV-related hepatic damage and fibrosis in HCC patients. J Exp Clin Cancer Res 2023; 42 (01) 152
    CrossrefPubMedGoogle Scholar
  • 148 Xie Z, Huang J, Li Y. et al. Single-cell RNA sequencing revealed potential targets for immunotherapy studies in hepatocellular carcinoma. Sci Rep 2023; 13 (01) 18799
    CrossrefPubMedGoogle Scholar