Function and regulatory mechanism of T lymphocytes in tumor immune microenvironment of hepatocellular carcinoma

Mengkui HAN; Jin LI; Xiaohua YANG

doi:10.3969/j.issn.1001-5256.2022.11.037

Volume 38 Issue 11

Nov. 2022

Turn off MathJax

Article Contents

Article Navigation > Journal of Clinical Hepatology > 2022 > 38(11): 2621-2626

PDF( 2540 KB)

Function and regulatory mechanism of T lymphocytes in tumor immune microenvironment of hepatocellular carcinoma

DOI: 10.3969/j.issn.1001-5256.2022.11.037

Mengkui HAN¹,
Jin LI²,
Xiaohua YANG^{1
,
,
,}

1.
Department of General Surgery, the First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215031, China
2.
Department of Clinical Laboratory, the Fifth People's Hospital of Suzhou, Suzhou, Jiangsu 215131, China

Research funding:

National Natural Science Foundation of China (81902054);

Science and Education Project of Suzhou (kjxw2018045);

Science and Technology Development Plan of Suzhou (SKJYD2021136);

Clinical Medicine Research Foundation of Yili (yl2021lh04)

More Information

Corresponding author: YANG Xiaohua, yxiaohua2022@163.com(ORCID: 0000-0002-1767-5499)
Received Date: 2022-04-03
Accepted Date: 2022-06-22
Published Date: 2022-11-20

Abstract

Abstract

As the key immune cells in tumor immune microenvironment, T lymphocytes can affect the proliferation and migration of hepatocellular carcinoma (HCC) cells and control tumor progression through the secretion of cytokines, cytotoxic enzymes (perforin, granzyme B), and other pathways. At the same time, immune cells such as dendritic cells and myeloid-derived suppressor cells in tumor immune microenvironment can regulate the immune function of different T cell subsets through various pathways. This article summarizes the influence of common immune cells in tumor immune microenvironment on the function of T lymphocytes and the mechanism of action of key signaling pathways associated with the functional regulation of T lymphocytes in HCC, so as to provide ideas and clues for developing better therapeutic strategies for HCC.
- Carcinoma, Hepatocellular,
- T Lymphocyte,
- Immune Microenvironment,
- Immunotherapy

FullText(HTML)

References(50)

References

[1]	BRAY F, FERLAY J, SOERJOMATARAM I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2018, 68(6): 394-424. DOI: 10.3322/caac.21492.
[2]	VOGEL A, SABOROWSKI A. Current strategies for the treatment of intermediate and advanced hepatocellular carcinoma[J]. Cancer Treat Rev, 2020, 82: 101946. DOI: 10.1016/j.ctrv.2019.101946.
[3]	LI XY, SHEN Y, ZHANG L, et al. Understanding initiation and progression of hepatocellular carcinoma through single cell sequencing[J]. Biochim Biophys Acta Rev Cancer, 2022, 1877(3): 188720. DOI: 10.1016/j.bbcan.2022.188720.
[4]	TOUGH DF, RIOJA I, MODIS LK, et al. Epigenetic regulation of T cell memory: Recalling therapeutic implications[J]. Trends Immunol, 2020, 41(1): 29-45. DOI: 10.1016/j.it.2019.11.008.
[5]	RAMZAN M, STURM N, DECAENS T, et al. Liver-infiltrating CD8⁺lymphocytes as prognostic factor for tumour recurrence in hepatitis C virus-related hepatocellular carcinoma[J]. Liver Int, 2016, 36(3): 434-444. DOI: 10.1111/liv.12927.
[6]	KHAN O, GILES JR, MCDONALD S, et al. TOX transcriptionally and epigenetically programs CD8⁺T cell exhaustion[J]. Nature, 2019, 571(7764): 211-218. DOI: 10.1038/s41586-019-1325-x.
[7]	BROWN ZJ, FU Q, MA C, et al. Carnitine palmitoyl transferase gene upregulation by linoleic acid induces CD4⁺T cell apoptosis promoting HCC development[J]. Cell Death Dis, 2018, 9(6): 620. DOI: 10.1038/s41419-018-0687-6.
[8]	DUTTA A, VENKATA GANESH H, LOVE PE. New insights into epigenetic regulation of T cell differentiation[J]. Cells, 2021, 10(12): 3459. DOI: 10.3390/cells10123459.
[9]	QUEZADA SA, SIMPSON TR, PEGGS KS, et al. Tumor-reactive CD4⁺T cells develop cytotoxic activity and eradicate large established melanoma after transfer into lymphopenic hosts[J]. J Exp Med, 2010, 207(3): 637-650. DOI: 10.1084/jem.20091918.
[10]	HUANG Y, LIAO H, ZHANG Y, et al. Prognostic value of tumor-infiltrating FoxP3⁺T cells in gastrointestinal cancers: a meta analysis[J]. PLoS One, 2014, 9(5): e94376. DOI: 10.1371/journal.pone.0094376.
[11]	ZHANG H, JIANG Z, ZHANG L. Dual effect of T helper cell 17 (Th17) and regulatory T cell (Treg) in liver pathological process: From occurrence to end stage of disease[J]. Int Immunopharmacol, 2019, 69: 50-59. DOI: 10.1016/j.intimp.2019.01.005.
[12]	LANGHANS B, NISCHALKE HD, KRÄMER B, et al. Role of regulatory T cells and checkpoint inhibition in hepatocellular carcinoma[J]. Cancer Immunol Immunother, 2019, 68(12): 2055-2066. DOI: 10.1007/s00262-019-02427-4.
[13]	HAN Y, CHEN Z, YANG Y, et al. Human CD14⁺CTLA-4⁺regulatory dendritic cells suppress T-cell response by cytotoxic T-lymphocyte antigen-4-dependent IL-10 and indoleamine-2, 3-dioxygenase production in hepatocellular carcinoma[J]. Hepatology, 2014, 59(2): 567-579. DOI: 10.1002/hep.26694.
[14]	ZHOU ZJ, XIN HY, LI J, et al. Intratumoral plasmacytoid dendritic cells as a poor prognostic factor for hepatocellular carcinoma following curative resection[J]. Cancer Immunol Immunother, 2019, 68(8): 1223-1233. DOI: 10.1007/s00262-019-02355-3.
[15]	CHEN X, DU Y, HU Q, et al. Tumor-derived CD4⁺CD25⁺regulatory T cells inhibit dendritic cells function by CTLA-4[J]. Pathol Res Pract, 2017, 213(3): 245-249. DOI: 10.1016/j.prp.2016.12.008.
[16]	ZHOU G, SPRENGERS D, BOOR PPC, et al. Antibodies against immune checkpoint molecules restore functions of tumor-infiltrating T cells in hepatocellular carcinomas[J]. Gastroenterology, 2017, 153(4): 1107-1119. e10. DOI: 10.1053/j.gastro.2017.06.017.
[17]	YU Z, LI Y, LI Y, et al. Bufalin stimulates antitumor immune response by driving tumor-infiltrating macrophage toward M1 phenotype in hepatocellular carcinoma[J]. J Immunother Cancer, 2022, 10(5): e004297. DOI: 10.1136/jitc-2021-004297.
[18]	LI X, YAO W, YUAN Y, et al. Targeting of tumour-infiltrating macrophages via CCL2/CCR2 signalling as a therapeutic strategy against hepatocellular carcinoma[J]. Gut, 2017, 66(1): 157-167. DOI: 10.1136/gutjnl-2015-310514.
[19]	PU J, XU Z, NIAN J, et al. M2 macrophage-derived extracellular vesicles facilitate CD8⁺T cell exhaustion in hepatocellular carcinoma via the miR-21-5p/YOD1/YAP/β-catenin pathway[J]. Cell Death Discov, 2021, 7(1): 182. DOI: 10.1038/s41420-021-00556-3.
[20]	WU Q, ZHOU W, YIN S, et al. Blocking triggering receptor expressed on myeloid cells-1-positive tumor-associated macrophages induced by hypoxia reverses immunosuppression and anti-programmed cell death ligand 1 resistance in liver cancer[J]. Hepatology, 2019, 70(1): 198-214. DOI: 10.1002/hep.30593.
[21]	PERANZONI E, LEMOINE J, VIMEUX L, et al. Macrophages impede CD8⁺T cells from reaching tumor cells and limit the efficacy of anti-PD-1 treatment[J]. Proc Natl Acad Sci U S A, 2018, 115(17): E4041-E4050. DOI: 10.1073/pnas.1720948115.
[22]	WANG N, TAN HY, LU Y, et al. PIWIL1 governs the crosstalk of cancer cell metabolism and immunosuppressive microenvironment in hepatocellular carcinoma[J]. Signal Transduct Target Ther, 2021, 6(1): 86. DOI: 10.1038/s41392-021-00485-8.
[23]	HSIEH CC, HUNG CH, CHIANG M, et al. Hepatic stellate cells enhance liver cancer progression by inducing myeloid-derived suppressor cells through interleukin-6 signaling[J]. Int J Mol Sci, 2019, 20(20): 5079. DOI: 10.3390/ijms20205079.
[24]	DYSTHE M, PARIHAR R. Myeloid-derived suppressor cells in the tumor microenvironment[J]. Adv Exp Med Biol, 2020, 1224: 117-140. DOI: 10.1007/978-3-030-35723-8_8.
[25]	TRAILIN A, ČERVENKOVÁ L, AMBROZKIEWICZ F, et al. T-and B-cells in the inner invasive margin of hepatocellular carcinoma after resection associate with favorable prognosis[J]. Cancers (Basel), 2022, 14(3): 604. DOI: 10.3390/cancers14030604.
[26]	SHI JY, GAO Q, WANG ZC, et al. Margin-infiltrating CD20⁺B cells display an atypical memory phenotype and correlate with favorable prognosis in hepatocellular carcinoma[J]. Clin Cancer Res, 2013, 19(21): 5994-6005. DOI: 10.1158/1078-0432.CCR-12-3497.
[27]	GARNELO M, TAN A, HER Z, et al. Interaction between tumour-infiltrating B cells and T cells controls the progression of hepatocellular carcinoma[J]. Gut, 2017, 66(2): 342-351. DOI: 10.1136/gutjnl-2015-310814.
[28]	FENG Y, LIU L, LI J, et al. Systematic characterization of the tumor microenvironment in Chinese patients with hepatocellular carcinoma highlights intratumoral B cells as a potential immunotherapy target[J]. Oncol Rep, 2022, 47(2): 38. DOI: 10.3892/or.2021.8249.
[29]	XUE H, LIN F, TAN H, et al. Overrepresentation of IL-10-expressing B cells suppresses cytotoxic CD4⁺T cell activity in HBV-induced hepatocellular carcinoma[J]. PLoS One, 2016, 11(5): e0154815. DOI: 10.1371/journal.pone.0154815.
[30]	RUIZ DE GALARRETA M, BRESNAHAN E, MOLINA-SÁNCHEZ P, et al. β-catenin activation promotes immune escape and resistance to anti-PD-1 therapy in hepatocellular carcinoma[J]. Cancer Discov, 2019, 9(8): 1124-1141. DOI: 10.1158/2159-8290.CD-19-0074.
[31]	SCHINZARI V, TIMPERI E, PECORA G, et al. Wnt3a/β-catenin signaling conditions differentiation of partially exhausted T-effector cells in human cancers[J]. Cancer Immunol Res, 2018, 6(8): 941-952. DOI: 10.1158/2326-6066.CIR-17-0712.
[32]	ZHU GQ, WANG Y, WANG B, et al. Targeting HNRNPM inhibits cancer stemness and enhances antitumor immunity in Wnt-activated hepatocellular carcinoma[J]. Cell Mol Gastroenterol Hepatol, 2022, 13(5): 1413-1447. DOI: 10.1016/j.jcmgh.2022.02.006.
[33]	TAURIELLO DVF, SANCHO E, BATLLE E. Overcoming TGFβ-mediated immune evasion in cancer[J]. Nat Rev Cancer, 2022, 22(1): 25-44. DOI: 10.1038/s41568-021-00413-6.
[34]	BATLLE E, MASSAGUÉ J. Transforming growth factor-β signaling in immunity and cancer[J]. Immunity, 2019, 50(4): 924-940. DOI: 10.1016/j.immuni.2019.03.024.
[35]	DIMELOE S, GUBSER P, LOELIGER J, et al. Tumor-derived TGF-β inhibits mitochondrial respiration to suppress IFN-γ production by human CD4⁺T cells[J]. Sci Signal, 2019, 12(599): eaav3334. DOI: 10.1126/scisignal.aav3334.
[36]	WANG X, HE Q, SHEN H, et al. TOX promotes the exhaustion of antitumor CD8⁺T cells by preventing PD1 degradation in hepatocellular carcinoma[J]. J Hepatol, 2019, 71(4): 731-741. DOI: 10.1016/j.jhep.2019.05.015.
[37]	DITURI F, MANCARELLA S, SERINO G, et al. Direct and indirect effect of TGFβ on treg transendothelial recruitment in HCC tissue microenvironment[J]. Int J Mol Sci, 2021, 22(21): 11765. DOI: 10.3390/ijms222111765.
[38]	HE G, YU GY, TEMKIN V, et al. Hepatocyte IKKbeta/NF-kappaB inhibits tumor promotion and progression by preventing oxidative stress-driven STAT3 activation[J]. Cancer Cell, 2010, 17(3): 286-297. DOI: 10.1016/j.ccr.2009.12.048.
[39]	CHENG JT, DENG YN, YI HM, et al. Hepatic carcinoma-associated fibroblasts induce IDO-producing regulatory dendritic cells through IL-6-mediated STAT3 activation[J]. Oncogenesis, 2016, 5(2): e198. DOI: 10.1038/oncsis.2016.7.
[40]	MIRLEKAR B, PYLAYEVA-GUPTA Y. IL-12 family cytokines in cancer and immunotherapy[J]. Cancers (Basel), 2021, 13(2): 167. DOI: 10.3390/cancers13020167.
[41]	NISHIDA N. Clinical implications of the dual blockade of the PD-1/PD-L1 and vascular endothelial growth factor axes in the treatment of hepatocellular carcinoma[J]. Hepatobiliary Surg Nutr, 2020, 9(5): 640-643. DOI: 10.21037/hbsn.2019.10.18.
[42]	EL-KHOUEIRY AB, SANGRO B, YAU T, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial[J]. Lancet, 2017, 389(10088): 2492-2502. DOI: 10.1016/S0140-6736(17)31046-2.
[43]	AGDASHIAN D, ELGINDI M, XIE C, et al. The effect of anti-CTLA4 treatment on peripheral and intra-tumoral T cells in patients with hepatocellular carcinoma[J]. Cancer Immunol Immunother, 2019, 68(4): 599-608. DOI: 10.1007/s00262-019-02299-8.
[44]	QIN S, REN Z, MENG Z, et al. Camrelizumab in patients with previously treated advanced hepatocellular carcinoma: a multicentre, open-label, parallel-group, randomised, phase 2 trial[J]. Lancet Oncol, 2020, 21(4): 571-580. DOI: 10.1016/S1470-2045(20)30011-5.
[45]	YAU T, KANG YK, KIM TY, et al. Efficacy and safety of nivolumab plus ipilimumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib: the CheckMate 040 randomized clinical trial[J]. JAMA Oncol, 2020, 6(11): e204564. DOI: 10.1001/jamaoncol.2020.4564.
[46]	GORABI AM, HAJIGHASEMI S, SATHYAPALAN T, et al. Cell transfer-based immunotherapies in cancer: A review[J]. IUBMB Life, 2020, 72(4): 790-800. DOI: 10.1002/iub.2180.
[47]	LEE JH, LEE JH, LIM YS, et al. Adjuvant immunotherapy with autologous cytokine-induced killer cells for hepatocellular carcinoma[J]. Gastroenterology, 2015, 148(7): 1383-1391. e6. DOI: 10.1053/j.gastro.2015.02.055.
[48]	SZOOR A, VAIDYA A, VELASQUEZ MP, et al. T cell-activating mesenchymal stem cells as a biotherapeutic for HCC[J]. Mol Ther Oncolytics, 2017, 6: 69-79. DOI: 10.1016/j.omto.2017.07.002.
[49]	LI J, HUANG S, ZHOU Z, et al. Exosomes derived from rAAV/AFP-transfected dendritic cells elicit specific T cell-mediated immune responses against hepatocellular carcinoma[J]. Cancer Manag Res, 2018, 10: 4945-4957. DOI: 10.2147/CMAR.S178326.
[50]	TANIGUCHI M, MIZUNO S, YOSHIKAWA T, et al. Peptide vaccine as an adjuvant therapy for glypican-3-positive hepatocellular carcinoma induces peptide-specific CTLs and improves long prognosis[J]. Cancer Sci, 2020, 111(8): 2747-2759. DOI: 10.1111/cas.14497.

Relative Articles

Supplements(0)

Cited By

Proportional views

Proportional views

通讯作者: 陈斌, bchen63@163.com

1.
沈阳化工大学材料科学与工程学院沈阳 110142

Figures(1)

Get Citation

PDF

XML

Article Metrics

Article views (524) PDF downloads(54)

Function and regulatory mechanism of T lymphocytes in tumor immune microenvironment of hepatocellular carcinoma

DOI: 10.3969/j.issn.1001-5256.2022.11.037

Abstract

References

Proportional views

Catalog

通讯作者: 陈斌, bchen63@163.com

Article Metrics

Proportional views

Related

Function and regulatory mechanism of T lymphocytes in tumor immune microenvironment of hepatocellular carcinoma

DOI: 10.3969/j.issn.1001-5256.2022.11.037

Abstract

References

Proportional views

Catalog

通讯作者: 陈斌, bchen63@163.com

Article Metrics

Proportional views

Related

About Journal

Submission Guideline

Journal Online

Hepatobiliary College

Guidelines

Export File

Citation

Format

Content