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New insights into T-cell exhaustion in liver cancer: from mechanism to therapy

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Abstract

Liver cancer is one of the most common malignancies. T-cell exhaustion is associated with immunosuppression of tumor and chronic infection. Although immunotherapies that enhance the immune response by targeting programmed cell death-1(PD-1)/programmed cell death ligand 1 (PD-L1) have been applied to malignancies, these treatments have shown limited response rates. This suggested that additional inhibitory receptors (IRs) also contributed to T-cell exhaustion and tumor prognosis. Exhausted T-cells (Tex) in the tumor immune microenvironment (TME) are usually in a dysfunctional state of exhaustion, such as impaired activity and proliferative ability, increased apoptosis rate, and reduced production of effector cytokines. Tex cells participate in the negative regulation of tumor immunity mainly through IRs on the cell surface, changes in cytokines and immunomodulatory cell types, causing tumor immune escape. However, T-cell exhaustion is not irreversible and targeted immune checkpoint inhibitors (ICIs) can effectively reverse the exhaustion of T-cells and restore the anti-tumor immune response. Therefore, the research on the mechanism of T-cell exhaustion in liver cancer, aimed at maintaining or restoring the effector function of Tex cells, might provide a new method for the treatment of liver cancer. In this review, we summarized the basic characteristics of Tex cells (such as IRs and cytokines), discussed the mechanisms associated with T-cell exhaustion, and specifically discussed how these exhaustion characteristics were acquired and shaped by key factors within TME. Then new insights into the molecular mechanism of T-cell exhaustion suggested a potential way to improve the efficacy of cancer immunotherapy, namely to restore the effector function of Tex cells. In addition, we also reviewed the research progress of T-cell exhaustion in recent years and provided suggestions for further research.

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Abbreviations

MTA:

5-Methylthioadenosine

ADORA1:

Adenosine A1 receptor

AGTRAP:

Angiotensin II receptor-associated protein

APCs:

Antigen-presenting cells

ARG1:

Arginase I

CEACAM-1:

Carcinoembryonic antigen-related cell adhesion molecule 1

CHB:

Chronic hepatitis B

CSF-1:

Colony stimulating factor 1

COX-2:

Cyclooxygenase-2

CTLA-4:

Cytotoxic T lymphocyte-associated antigen-4

CTLs:

Cytotoxic T lymphocytes

Eomes:

Eomesodermin

Tex:

Exhausted T-cells

eADO:

Extracellular adenosine

FGL-1:

Fibrinogen-like protein 1

Gal-9:

Galactose lectin 9

GLIS1:

GLI-similar 1

GPNMB:

Glycoprotein nonmetastatic melanoma protein B

HBV:

Hepatitis B virus

HCV:

Hepatitis C virus

HCC:

Hepatocellular carcinoma

HMGB1:

High mobility group box-1 protein

ICIs:

Immune checkpoint inhibitors

ICIs:

Immune checkpoint inhibitors

IRs:

Inhibitory receptors

IRF 8:

Interferon regulatory factor 8

IFN-γ:

Interferon-γ

IL-2:

Interleukin-2

KPNA4:

Karyopherin α4

LAYN:

Layilin

LAG-3:

Lymphocyte-activation gene 3

LCMV:

Lymphocytic choriomeningitis virus

MDZ:

Midazolam

MRS:

Myeloid response scores

MDSCs:

Myeloid-derived suppressor cells

NETs:

Neutrophil extracellular traps

NASH:

Non-alcoholic steatohepatitis

NTME:

Nontumor microenvironment

NuRD:

Nucleosome remodeling and deacetylase

PtdSer:

Phosphatidylserine

pDCs:

Plasmacytoid dendritic cells

PD-L1:

Programmed cell death ligand 1

PD-1:

Programmed cell death-1

PGE-2:

Prostaglandin E-2

PTP1B:

Protein-tyrosine phosphatase 1B

RBPJ:

Recombination signal binding protein for immunoglobulin kappa J region

Tregs:

Regulatory T-cell

SAM:

S-adenosylmethionine

sTIM-3:

Soluble TIM-3

SPAG5:

Sperm-associated antigen 5

TBK1:

TANK-Binding Kinase 1

TIGIT:

T-cell Ig and ITIM domain

TIM-3:

T-cell immunoglobulin and mucin-domain containing-3

TOX:

Thymocyte selection-associated high mobility group-box protein

TGF-β1:

Transforming growth factor beta 1

TECs:

Tumor endothelial cells

TME:

Tumor immune microenvironment

TNF-α:

Tumor necrosis factor-α

TAMs:

Tumor-associated macrophages

TANs:

Tumor-associated neutrophils

TILs:

Tumor-infiltrating lymphocyte

TST:

Tumor-specific CD8+T-cells

XDH:

Xanthine dehydrogenase

YTHDF2:

YTH domain family 2

References

  • Andrews LP, Marciscano AE, Drake CG, Vignali DA (2017) LAG3 (CD223) as a cancer immunotherapy target. Immunol Rev 276:80–96

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bai X et al (2022) Adaptive antitumor immune response stimulated by bio-nanoparticle based vaccine and checkpoint blockade. J Exp Clin Cancer Res 41:022–02307

    Google Scholar 

  • Bao S, Jiang X, Jin S, Tu P, Lu J (2021) TGF-β1 Induces immune escape by enhancing PD-1 and CTLA-4 expression on T lymphocytes in hepatocellular carcinoma. Front Oncol 11.

  • Barsch M et al (2022) T-cell exhaustion and residency dynamics inform clinical outcomes in hepatocellular carcinoma. J Hepatol 77:397–409

    CAS  PubMed  Google Scholar 

  • Buggert M et al. (2014) T-bet and Eomes are differentially linked to the exhausted phenotype of CD8+ T cells in HIV infection. PLoS Pathog 10.

  • Cai L et al (2008) Functional impairment in circulating and intrahepatic NK cells and relative mechanism in hepatocellular carcinoma patients. Clin Immunol 129:428–437

    CAS  PubMed  Google Scholar 

  • Cham CM, Gajewski TF (2005) Glucose availability regulates IFN-gamma production and p70S6 kinase activation in CD8+ effector T cells. J Immunol 174:4670–4677

    CAS  PubMed  Google Scholar 

  • Chang CH et al (2015) Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 162:1229–1241

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chauvin JM, Zarour HM (2020) TIGIT in cancer immunotherapy. J Immunother Cancer 8:2020–000957

    Google Scholar 

  • Chen DS, Mellman I (2013) Oncology meets immunology: the cancer-immunity cycle. Immunity 39:1–10

    PubMed  Google Scholar 

  • Chen Z et al (2020a) Recent progress in treatment of hepatocellular carcinoma. Am J Cancer Res 10:2993–3036

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chen W, Chen X, Li S, Ren B (2020b) Expression, immune infiltration and clinical significance of SPAG5 in hepatocellular carcinoma: a gene expression-based study. J Gene Med 22:27

    Google Scholar 

  • Cheng Y et al (2021) Non-terminally exhausted tumor-resident memory HBV-specific T cell responses correlate with relapse-free survival in hepatocellular carcinoma. Immunity 54:1825–1840

    CAS  PubMed  Google Scholar 

  • Chew V et al (2017) Delineation of an immunosuppressive gradient in hepatocellular carcinoma using high-dimensional proteomic and transcriptomic analyses. Proc Natl Acad Sci USA 114:E5900–E5909

    CAS  PubMed  PubMed Central  Google Scholar 

  • Cui S et al. (2023) Development of prognostic features of hepatocellular carcinoma based on metabolic gene classification and immune and oxidative stress characteristic analysis. Oxid Med Cell Longev 18.

  • Deng Z et al (2021) Key candidate prognostic biomarkers correlated with immune infiltration in hepatocellular carcinoma. J Hepatocell Carcinoma 8:1607–1622

    CAS  PubMed  PubMed Central  Google Scholar 

  • Dong P et al. (2016) CD86+/CD206+, diametrically polarized tumor-associated macrophages, predict hepatocellular carcinoma patient prognosis. Int J Mol Sci 17.

  • EASL Clinical Practice Guidelines (2018) Management of hepatocellular carcinoma. J Hepatol 69:182–236

    Google Scholar 

  • Facciabene A et al (2011) Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and T(reg) cells. Nature 475:226–230

    CAS  PubMed  Google Scholar 

  • Fisicaro P et al (2017) Targeting mitochondrial dysfunction can restore antiviral activity of exhausted HBV-specific CD8 T cells in chronic hepatitis B. Nat Med 23:327–336

    CAS  PubMed  Google Scholar 

  • Fletcher M et al (2015) l-Arginine depletion blunts antitumor T-cell responses by inducing myeloid-derived suppressor cells. Cancer Res 75:275–283

    CAS  PubMed  Google Scholar 

  • Fourcade J et al (2010) Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CD8+ T cell dysfunction in melanoma patients. J Exp Med 207:2175–2186

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gabrilovich DI, Nagaraj S (2009) Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 9:162–174

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gao Y et al (2022) Heterogeneity induced GZMA-F2R communication inefficient impairs antitumor immunotherapy of PD-1 mAb through JAK2/STAT1 signal suppression in hepatocellular carcinoma. Cell Death Dis 13:022–04654

    Google Scholar 

  • Garrido F, Cabrera T, Aptsiauri N (2010) “Hard” and “soft” lesions underlying the HLA class I alterations in cancer cells: implications for immunotherapy. Int J Cancer 127:249–256

    CAS  PubMed  Google Scholar 

  • Ge Z et al (2021) TIGIT and PD1 Co-blockade restores ex vivo functions of human tumor-infiltrating CD8(+) T cells in hepatocellular carcinoma. Cell Mol Gastroenterol Hepatol 12:443–464

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gehring AJ et al (2009) Profile of tumor antigen-specific CD8 T cells in patients with hepatitis B virus-related hepatocellular carcinoma. Gastroenterology 137:682–690

    CAS  PubMed  Google Scholar 

  • Ghoneim HE et al (2017) De novo epigenetic programs inhibit PD-1 blockade-mediated T cell rejuvenation. Cell 170:142–157

    CAS  PubMed  PubMed Central  Google Scholar 

  • Giraud J, Chalopin D, Blanc JF, Saleh M (2021) Hepatocellular carcinoma immune landscape and the potential of immunotherapies. Front Immunol 12.

  • Gu Y et al (2020) CCL14 is a prognostic biomarker and correlates with immune infiltrates in hepatocellular carcinoma. Aging 12:784–807

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674

    CAS  PubMed  Google Scholar 

  • He H et al (2021) Down-regulation of EOMES drives T-cell exhaustion via abolishing EOMES-mediated repression of inhibitory receptors of T cells in liver cancer. J Cell Mol Med 25:161–169

    CAS  PubMed  Google Scholar 

  • He J, Meng M, Wang H (2022) A novel prognostic biomarker LPAR6 in hepatocellular carcinoma via associating with immune infiltrates. J Clin Transl Hepatol 10:90–103

    PubMed  Google Scholar 

  • Hsu CL et al (2021) Exploring markers of exhausted CD8 T cells to predict response to immune checkpoint inhibitor therapy for hepatocellular carcinoma. Liver Cancer 10:346–359

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hung MH et al (2021) Tumor methionine metabolism drives T-cell exhaustion in hepatocellular carcinoma. Nat Commun 12:021–21804

    Google Scholar 

  • Ji J et al (2018) Long non-coding RNA Lnc-Tim3 exacerbates CD8 T cell exhaustion via binding to Tim-3 and inducing nuclear translocation of Bat3 in HCC. Cell Death Dis 9:018–0528

    Google Scholar 

  • Jiang Y et al. (2021) TANK-Binding Kinase 1 (TBK1) Serves as a Potential target for hepatocellular carcinoma by enhancing tumor immune infiltration. Front Immunol 12.

  • Jin H et al (2022a) New insights into checkpoint inhibitor immunotherapy and its combined therapies in hepatocellular carcinoma: from mechanisms to clinical trials. Int J Biol Sci 18:2775–2794

    CAS  PubMed  PubMed Central  Google Scholar 

  • Jin Y et al (2022b) Expression of Id3 represses exhaustion of anti-tumor CD8 T cells in liver cancer. Mol Immunol 144:117–126

    CAS  PubMed  Google Scholar 

  • Johnston RJ et al (2014) The immunoreceptor TIGIT regulates antitumor and antiviral CD8(+) T cell effector function. Cancer Cell 26:923–937

    CAS  PubMed  Google Scholar 

  • Kaech SM, Cui W (2012) Transcriptional control of effector and memory CD8+ T cell differentiation. Nat Rev Immunol 12:749–761

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kaltenmeier C et al. (2021) Neutrophil extracellular traps promote T cell exhaustion in the tumor microenvironment. Front Immunol 12.

  • Kang J et al (2022) Midazolam exhibits antitumour and enhances the efficiency of Anti-PD-1 immunotherapy in hepatocellular carcinoma. Cancer Cell Int 22:022–02735

    Google Scholar 

  • Kato Y et al. (2019) Lenvatinib plus anti-PD-1 antibody combination treatment activates CD8+ T cells through reduction of tumor-associated macrophage and activation of the interferon pathway. PLoS One 14.

  • Kelly C et al (2016) Chronic hepatitis C viral infection subverts vaccine-induced T-cell immunity in humans. Hepatology 63:1455–1470

    CAS  PubMed  Google Scholar 

  • Khan M, Arooj S, Wang H (2020) NK cell-based immune checkpoint inhibition. Front Immunol 11.

  • Kim HD et al (2020) 4–1BB delineates distinct activation status of exhausted tumor-infiltrating CD8(+) T cells in hepatocellular carcinoma. Hepatology 71:955–971

    CAS  PubMed  Google Scholar 

  • Kitamura T, Qian BZ, Pollard JW (2015) Immune cell promotion of metastasis. Nat Rev Immunol 15:73–86

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kotanides H et al (2020) Bispecific targeting of PD-1 and PD-L1 enhances T-cell activation and antitumor immunity. Cancer Immunol Res 8:1300–1310

    PubMed  Google Scholar 

  • Kučan Brlić, P et al. (2019) Targeting PVR (CD155) and its receptors in anti-tumor therapy. Cell Mol Immunol 16: 40–52.

  • Kumar V, Patel S, Tcyganov E, Gabrilovich DI (2016) The nature of myeloid-derived suppressor cells in the tumor microenvironment. Trends Immunol 37:208–220

    CAS  PubMed  PubMed Central  Google Scholar 

  • Laidlaw BJ, Craft JE, Kaech SM (2016) The multifaceted role of CD4(+) T cells in CD8(+) T cell memory. Nat Rev Immunol 16:102–111

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lawal G et al. (2021) The Immunology of Hepatocellular Carcinoma. Vaccines 9.

  • Li Z et al (2012a) TIM3 gene polymorphisms in patients with chronic hepatitis B virus infection: impact on disease susceptibility and hepatocellular carcinoma traits. Tissue Antigens 80:151–157

    CAS  PubMed  Google Scholar 

  • Li T et al (2012b) Hepatocellular carcinoma-associated fibroblasts trigger NK cell dysfunction via PGE2 and IDO. Cancer Lett 318:154–161

    CAS  PubMed  Google Scholar 

  • Li F et al (2018a) Highly elevated soluble Tim-3 levels correlate with increased hepatocellular carcinoma risk and poor survival of hepatocellular carcinoma patients in chronic hepatitis B virus infection. Cancer Manag Res 10:941–951

    CAS  PubMed  PubMed Central  Google Scholar 

  • Li J et al (2018b) Co-inhibitory molecule B7 superfamily member 1 expressed by tumor-infiltrating myeloid cells induces dysfunction of anti-tumor CD8(+) T cells. Immunity 48:773–786

    CAS  PubMed  Google Scholar 

  • Li Q et al (2022) PRDM1/BLIMP1 induces cancer immune evasion by modulating the USP22-SPI1-PD-L1 axis in hepatocellular carcinoma cells. Nat Commun 13:022–35469

    Google Scholar 

  • Lim CJ et al (2019) Multidimensional analyses reveal distinct immune microenvironment in hepatitis B virus-related hepatocellular carcinoma. Gut 68:916–927

    CAS  PubMed  Google Scholar 

  • Lin Z et al (2021) Xanthine dehydrogenase as a prognostic biomarker related to tumor immunology in hepatocellular carcinoma. Cancer Cell Int 21:021–02173

    Google Scholar 

  • Linsley PS et al (1991) Binding of the B cell activation antigen B7 to CD28 costimulates T cell proliferation and interleukin 2 mRNA accumulation. J Exp Med 173:721–730

    CAS  PubMed  Google Scholar 

  • Liu Y, Zheng P (2020) Preserving the CTLA-4 checkpoint for safer and more effective cancer immunotherapy. Trends Pharmacol Sci 41:4–12

    CAS  PubMed  Google Scholar 

  • Liu YT et al (2018) A novel spontaneous hepatocellular carcinoma mouse model for studying T-cell exhaustion in the tumor microenvironment. J Immunother Cancer 6:018–0462

    Google Scholar 

  • Liu X et al (2019a) PD-1(+) TIGIT(+) CD8(+) T cells are associated with pathogenesis and progression of patients with hepatitis B virus-related hepatocellular carcinoma. Cancer Immunol Immunother 68:2041–2054

    CAS  PubMed  Google Scholar 

  • Liu B et al (2019b) The lineage stability and suppressive program of regulatory T cells require protein O-GlcNAcylation. Nat Commun 10:019–08300

    CAS  Google Scholar 

  • Liu X, Ren H, Guo H, Wang W, Zhao N (2021) Interleukin-35 has a tumor-promoting role in hepatocellular carcinoma. Clin Exp Immunol 203:219–229

    CAS  PubMed  Google Scholar 

  • Liu F et al. (2020) Heterogeneity of exhausted T cells in the tumor microenvironment is linked to patient survival following resection in hepatocellular carcinoma. Oncoimmunology 9.

  • Liu SC et al. (2020) Research progress of CD8+T cell exhaustion mechanism and immunotherapy in hepatocellular carcinoma. Journal of Mudanjiang Medical University 41: 97-100, https://doi.org/10.13799/j.cnki.mdjyxyxb.2020.04.026 (2020).(in Chinese)

  • Liu S et al. (2021) AGTRAP Is a Prognostic biomarker correlated with immune infiltration in hepatocellular carcinoma. Front Oncol 11.

  • Lonberg N, Korman AJ (2017) Masterful antibodies: checkpoint blockade. Cancer Immunol Res 5:275–281

    PubMed  Google Scholar 

  • Lu Y et al (2022) A single-cell atlas of the multicellular ecosystem of primary and metastatic hepatocellular carcinoma. Nat Commun 13:022–32283

    Google Scholar 

  • Ma J et al (2019) PD1(Hi) CD8(+) T cells correlate with exhausted signature and poor clinical outcome in hepatocellular carcinoma. J Immunother Cancer 7:019–0814

    Google Scholar 

  • Mamrot J, Balachandran S, Steele EJ, Lindley RA (2019) Molecular model linking Th2 polarized M2 tumour-associated macrophages with deaminase-mediated cancer progression mutation signatures. Scand J Immunol 89:18

    Google Scholar 

  • Nishida N et al (2020) Association between genetic and immunological background of hepatocellular carcinoma and expression of programmed cell death-1. Liver Cancer 9:426–439

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ostroumov D et al (2021) Transcriptome profiling identifies TIGIT as a marker of T-cell exhaustion in liver cancer. Hepatology 73:1399–1418

    CAS  PubMed  Google Scholar 

  • Ouyang FZ et al. (2016) Dendritic cell-elicited B-cell activation fosters immune privilege via IL-10 signals in hepatocellular carcinoma. Nat Commun 7.

  • Pan B et al (2023) Targeted inhibition of RBPJ transcription complex alleviates the exhaustion of CD8(+) T cells in hepatocellular carcinoma. Commun Biol 6:023–04521

    Google Scholar 

  • Pang L et al (2021) Plasmacytoid dendritic cells recruited by HIF-1α/eADO/ADORA1 signaling induce immunosuppression in hepatocellular carcinoma. Cancer Lett 522:80–92

    CAS  PubMed  Google Scholar 

  • Patsoukis N et al. (2015) PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation. Nat Commun 6.

  • Pauken KE, Wherry EJ (2015) Overcoming T cell exhaustion in infection and cancer. Trends Immunol 36:265–276

    CAS  PubMed  PubMed Central  Google Scholar 

  • Qian BZ, Pollard JW (2010) Macrophage diversity enhances tumor progression and metastasis. Cell 141:39–51

    CAS  PubMed  PubMed Central  Google Scholar 

  • Reading JL et al (2018) The function and dysfunction of memory CD8(+) T cells in tumor immunity. Immunol Rev 283:194–212

    CAS  PubMed  Google Scholar 

  • Rong D et al (2023) GLIS1 intervention enhances anti-PD1 therapy for hepatocellular carcinoma by targeting SGK1-STAT3-PD1 pathway. J Immunother Cancer 11:2022–005126

    Google Scholar 

  • Sakano Y et al (2022) Tumor endothelial cell-induced CD8(+) T-cell exhaustion via GPNMB in hepatocellular carcinoma. Cancer Sci 113:1625–1638

    CAS  PubMed  PubMed Central  Google Scholar 

  • Saraiva M, Vieira P, O’Garra A (2020) Biology and therapeutic potential of interleukin-10. J Exp Med 217:20190418

    Google Scholar 

  • Schietinger A et al (2016) Tumor-Specific T Cell Dysfunction Is a Dynamic Antigen-Driven Differentiation Program Initiated Early during Tumorigenesis. Immunity 45:389–401

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sen DR et al (2016) The epigenetic landscape of T cell exhaustion. Science 354:1165–1169

    CAS  PubMed  PubMed Central  Google Scholar 

  • Shao XY, Dong J, Zhang H, Wu YS, Zheng L (2020) Systematic analyses of the role of the reader protein of N (6)-methyladenosine RNA methylation, YTH domain family 2, in liver hepatocellular carcinoma. Front Mol Biosci 7.

  • Shen Q et al (2017) Lipid metabolic characteristics of functionally exhausted CD8+ T cells in tumor microenvironment of hepatocellular carcinoma. Chin J Clin Med 24:514–518 ((in Chinese))

    Google Scholar 

  • Sheng H et al (2020) ATR inhibitor AZD6738 enhances the antitumor activity of radiotherapy and immune checkpoint inhibitors by potentiating the tumor immune microenvironment in hepatocellular carcinoma. J Immunother Cancer 8:2019–000340

    Google Scholar 

  • Simoni Y et al (2018) Bystander CD8(+) T cells are abundant and phenotypically distinct in human tumour infiltrates. Nature 557:575–579

    CAS  PubMed  Google Scholar 

  • Stephen TL et al (2017) SATB1 expression governs epigenetic repression of PD-1 in tumor-reactive T cells. Immunity 46:51–64

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sun C et al (2018) Oncofetal gene SALL4 reactivation by hepatitis B virus counteracts miR-200c in PD-L1-induced T cell exhaustion. Nat Commun 9:018–03584

    Google Scholar 

  • Sung H et al (2021) Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 71:209–249

    PubMed  Google Scholar 

  • Tan S et al (2020) Tim-3 hampers tumor surveillance of liver-resident and conventional NK cells by disrupting PI3K signaling. Cancer Res 80:1130–1142

    CAS  PubMed  Google Scholar 

  • Tomiyama T et al (2022) Myeloid-derived suppressor cell infiltration is associated with a poor prognosis in patients with hepatocellular carcinoma. Oncol Lett 23:27

    Google Scholar 

  • Topalian SL, Taube JM, Pardoll DM (2020) Neoadjuvant checkpoint blockade for cancer immunotherapy. Science 367.

  • Twyman-Saint Victor C et al. (2015) Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature 520: 373–377.

  • Villanueva A (2019) Hepatocellular carcinoma. N Engl J Med 380:1450–1462

    CAS  PubMed  Google Scholar 

  • Wang K, Karin M (2015) Tumor-elicited inflammation and colorectal cancer. Adv Cancer Res 128:173–196

    CAS  PubMed  Google Scholar 

  • Wang X, Lu XJ, Sun B (2017) The pros and cons of dying tumour cells in adaptive immune responses. Nat Rev Immunol 17:31

    Google Scholar 

  • Wang X et al (2018) 14-3-3ζ delivered by hepatocellular carcinoma-derived exosomes impaired anti-tumor function of tumor-infiltrating T lymphocytes. Cell Death Dis 9:017–0180

    CAS  Google Scholar 

  • Wang X et al (2019a) TOX promotes the exhaustion of antitumor CD8(+) T cells by preventing PD1 degradation in hepatocellular carcinoma. J Hepatol 71:731–741

    CAS  PubMed  Google Scholar 

  • Wang X, He Q, Shen H, Lu XJ, Sun B (2019b) Genetic and phenotypic difference in CD8(+) T cell exhaustion between chronic hepatitis B infection and hepatocellular carcinoma. J Med Genet 56:18–21

    PubMed  Google Scholar 

  • Wang J et al (2019c) Fibrinogen-like protein 1 Is a major immune inhibitory ligand of LAG-3. Cell 176:334–347

    CAS  PubMed  Google Scholar 

  • Wang YG, Zheng DH, Shi M, Xu XM (2019d) T cell dysfunction in chronic hepatitis B infection and liver cancer: evidence from transcriptome analysis. J Med Genet 56:22–28

    CAS  PubMed  Google Scholar 

  • Wang D et al (2019e) Macrophage-derived CCL22 promotes an immunosuppressive tumor microenvironment via IL-8 in malignant pleural effusion. Cancer Lett 452:244–253

    CAS  PubMed  Google Scholar 

  • Wang X et al (2019f) Exosomes derived from exhausted CD8+ T cells impaired the anticancer function of normal CD8+ T cells. J Med Genet 56:29–31

    CAS  PubMed  Google Scholar 

  • Wang XC (2019) Study on the mechanism of CD8+T cell depletion in invasive liver cancer. Nanjing Medical University. (in Chinese)

  • Wherry EJ, Kurachi M (2015) Molecular and cellular insights into T cell exhaustion. Nat Rev Immunol 15:486–499

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wolf Y, Anderson AC, Kuchroo VK (2020) TIM3 comes of age as an inhibitory receptor. Nat Rev Immunol 20:173–185

    CAS  PubMed  Google Scholar 

  • Woo SR et al (2012) Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res 72:917–927

    CAS  PubMed  Google Scholar 

  • Wu X et al (2019) Application of PD-1 Blockade in Cancer Immunotherapy. Comput Struct Biotechnol J 17:661–674

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wu C et al (2020) Myeloid signature reveals immune contexture and predicts the prognosis of hepatocellular carcinoma. J Clin Invest 130:4679–4693

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wu SY et al (2021a) Correlation of MKI67 with prognosis, immune infiltration, and T cell exhaustion in hepatocellular carcinoma. BMC Gastroenterol 21:021–01984

    Google Scholar 

  • Wu M, Xia X, Hu J, Fowlkes NW, Li S (2021b) WSX1 act as a tumor suppressor in hepatocellular carcinoma by downregulating neoplastic PD-L1 expression. Nat Commun 12:021–23864

    Google Scholar 

  • Wu H et al (2022) Hepatic interferon regulatory factor 8 expression suppresses hepatocellular carcinoma progression and enhances the response to anti-programmed cell death protein-1 therapy. Hepatology 76:1602–1616

    CAS  PubMed  Google Scholar 

  • Wu Y et al (2023) Blockade of T-cell receptor with Ig and ITIM domains elicits potent antitumor immunity in naturally occurring HBV-related HCC in mice. Hepatology 77:965–981

    PubMed  Google Scholar 

  • Xu M et al (2017) Interactions between interleukin-6 and myeloid-derived suppressor cells drive the chemoresistant phenotype of hepatocellular cancer. Exp Cell Res 351:142–149

    CAS  PubMed  Google Scholar 

  • Xu W, Atkins MB, McDermott DF (2020) Checkpoint inhibitor immunotherapy in kidney cancer. Nat Rev Urol 17:137–150

    CAS  PubMed  Google Scholar 

  • Xu M et al (2021) Value of KPNA4 as a diagnostic and prognostic biomarker for hepatocellular carcinoma. Aging 13:5263–5283

    CAS  PubMed  PubMed Central  Google Scholar 

  • Xu Y et al. (2020) DHX37 Impacts Prognosis of hepatocellular carcinoma and lung adenocarcinoma through immune infiltration. J Immunol Res 30.

  • Xun X et al (2021) Cyclooxygenase-2 expressed hepatocellular carcinoma induces cytotoxic T lymphocytes exhaustion through M2 macrophage polarization. Am J Transl Res 13:4360–4375

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yang Y et al (2018) Crosstalk between hepatic tumor cells and macrophages via Wnt/β-catenin signaling promotes M2-like macrophage polarization and reinforces tumor malignant behaviors. Cell Death Dis 9:018–0818

    Google Scholar 

  • Yang Y et al (2020) Analysis of single-cell RNAseq identifies transitional states of T cells associated with hepatocellular carcinoma. Clin Transl Med 10:13

    PubMed  PubMed Central  Google Scholar 

  • Yang R et al (2021) Galectin-9 interacts with PD-1 and TIM-3 to regulate T cell death and is a target for cancer immunotherapy. Nat Commun 12:021–21099

    Google Scholar 

  • Yang C et al. (2023) Fibrinogen-like protein 1 promotes liver-resident memory T-cell exhaustion in hepatocellular carcinoma. Front Immunol 14.

  • Yatim N, Cullen S, Albert ML (2017) Dying cells actively regulate adaptive immune responses. Nat Rev Immunol 17:262–275

    CAS  PubMed  Google Scholar 

  • Yazdani HO, Tohme S (2019) Murine model of metastatic liver tumors in the setting of ischemia reperfusion injury. J vis Exp 30:59748

    Google Scholar 

  • Yin C et al. (2019) SALL4-mediated upregulation of exosomal miR-146a-5p drives T-cell exhaustion by M2 tumor-associated macrophages in HCC. Oncoimmunology 8.

  • Yuan RL, Zheng MJ, Chen ZX, Xu YH (2021) TIM-3+TIGIT+CD4+T cell and TIM-3+TIGIT+CD8+T cell immune exhaustion in patients with hepatocellular carcinoma and its relationship with disease progression. Acta Universitatis Medicinalis Anhui 56: 1980–1986, https://doi.org/10.19405/j.cnki.issn1000-1492.2021.12.025.(in Chinese)

  • Zajac AJ et al (1998) Viral immune evasion due to persistence of activated T cells without effector function. J Exp Med 188:2205–2213

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang X et al (2004) Structural and functional analysis of the costimulatory receptor programmed death-1. Immunity 20:337–347

    CAS  PubMed  Google Scholar 

  • Zhang J, Shi Z, Xu X, Yu Z, Mi J (2019) The influence of microenvironment on tumor immunotherapy. Febs J 286:4160–4175

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang C et al (2020a) TIGIT can exert immunosuppressive effects on CD8+ T cells by the CD155/TIGIT signaling pathway for hepatocellular carcinoma in vitro. J Immunother 43:236–243

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang W et al (2020b) IL-6 promotes PD-L1 expression in monocytes and macrophages by decreasing protein tyrosine phosphatase receptor type O expression in human hepatocellular carcinoma. J Immunother Cancer 8:2019–000285

    Google Scholar 

  • Zhang P et al (2022) Neuregulin 4 suppresses NASH-HCC development by restraining tumor-prone liver microenvironment. Cell Metab 34:1359–1376

    CAS  PubMed  Google Scholar 

  • Zheng C et al (2017) Landscape of Infiltrating T Cells in Liver Cancer Revealed by Single-Cell Sequencing. Cell 169:1342–1356

    CAS  PubMed  Google Scholar 

  • Zhu Y et al (2022) The combination of PD-1 blockade with interferon-α has a synergistic effect on hepatocellular carcinoma. Cell Mol Immunol 19:726–737

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhu Y, Zu Y (2023) Comprehensive bioinformatics analysis reveals PTPN1 (PTP1B) is a promising immunotherapy target associated with T cell function for liver cancer. J Healthc Eng 27.

  • Zou F et al (2021) The CD39(+) HBV surface protein-targeted CAR-T and personalized tumor-reactive CD8(+) T cells exhibit potent anti-HCC activity. Mol Ther 29:1794–1807

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors acknowledge using Biorender (https://app.biorender.com/user/signin) to create the schemata (Figs. 2, 3).

Funding

The present study was financially supported by the National Natural Science Foundation of China (No. 81973840 and No. 81273748); National Science and Technology major projects of the 13th Five-Year Plan (2018ZX10303502); Science and Technology Program of Hebei (223777156D); Sichuan Provincial Administration of Traditional Chinese Medicine Major science and technology projects (2021XYCZ004).

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Authors and Affiliations

  1. Chengdu University of Traditional Chinese Medicine, No. 37 Shi-Er-Qiao Road, Chengdu, 610075, Sichuan Province, People’s Republic of China

    Liyuan Hao & Shenghao Li

  2. Hospital of Chengdu University of Traditional Chinese Medicine, No. 39 Shi-Er-Qiao Road, Chengdu, 610072, Sichuan Province, People’s Republic of China

    Liyuan Hao, Shenghao Li & Xiaoyu Hu

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  1. Liyuan Hao
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  2. Shenghao Li
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  3. Xiaoyu Hu
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XH designed the research; LH and SL wrote the manuscript with contributions from all authors. All authors read and approved the initial manuscript.

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Correspondence to Xiaoyu Hu.

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Hao, L., Li, S. & Hu, X. New insights into T-cell exhaustion in liver cancer: from mechanism to therapy. J Cancer Res Clin Oncol 149, 12543–12560 (2023). https://doi.org/10.1007/s00432-023-05083-5

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