Expression of interleukin-33 in hepatocellular carcinoma patients and its role in regulating CD8<sup>+</sup> T cell function

Haipeng WANG; Yi LIU; Donghui LI; Guanghui SHEN

doi:10.3969/j.issn.1001-5256.2022.01.018

Volume 38 Issue 1

Jan. 2022

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Expression of interleukin-33 in hepatocellular carcinoma patients and its role in regulating CD8⁺ T cell function

DOI: 10.3969/j.issn.1001-5256.2022.01.018

1.
Department of Medical Oncology, Shaanxi Provincial People's Hospital, Xi'an 710068, China
2.
Third Ward of Oncology, The Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang, Shaanxi 712000, China

Research funding:

Scientific Plan Program of Xi’an (2019114613YX011S f 035(3));

Basic Program of Xi’an Jiaotong University (XZY012019112);

National Natural Science Foundation of China (81402012)

Received Date: 2021-06-19
Accepted Date: 2021-07-29
Published Date: 2022-01-20

Abstract

Abstract

Objective To investigate the change in interleukin-33 (IL-33) in the peripheral blood of hepatocellular carcinoma (HCC) patients and the role and potential mechanism of IL-33 in regulating CD8⁺ T cell function in HCC patients. Methods A total of 44 HCC patients who attended Shaanxi Provincial People's Hospital from April 2019 to January 2020 and 20 healthy controls were enrolled. Peripheral blood was collected, and plasma and peripheral blood mononucleated cells (PBMCs) were isolated; ELISA was used to measure the plasma levels of IL-33 and its receptor ST2, and quantitative real-time PCR was used to measure the relative mRNA expression levels of IL-33 and ST2 in PBMCs. CD8⁺ T cells were purified and stimulated with recombinant IL-33; CCK-8 assay was used to assess cell proliferation, enzyme-linked immunospot assay was used to measure the secretion of perforin and granzyme B, and flow cytometry was used to measure the expression of PD-1, LAG-3, and CTLA-4; changes in cell proliferation, secretion of cytotoxic molecules, and immune checkpoint molecules after IL-33 stimulation were compared. CD8⁺ T cells were co-cultured with HepG2 cells; the expression of lactate dehydrogenase was measured to calculate the proportion of dead HepG2 cells induced by CD8⁺ T cells, and the change in the killing function of CD8⁺ T cells after IL-33 stimulation was compared. The t-test or the paired t-test was used for comparison of continuous data between two groups, and a Pearson correlation analysis was performed. Results Compared with the control group, the HCC group had significantly lower plasma level of IL-33 (269.80±63.08 pg/ml vs 339.50±64.43 pg/ml, t=4.072, P < 0.001) and relative mRNA expression level of IL-33 in PBMCs (1.07±0.14 vs 2.45±0.87, t=10.250, P < 0.001). There were no significant differences in the plasma level of ST2 and the relative mRNA expression level of ST2 in PBMCs between the HCC group and the control group (P > 0.05). The proportion of CD8⁺ T cells was not correlated with the plasma level of IL-33 or ST2 (both P > 0.05). Compared with the control group, the HCC group had significantly lower levels of perforin and granzyme B (both P < 0.05) and a significantly higher proportion of CD8⁺ T cells with positive PD-1, LAG-3, and CTLA-4 (P < 0.05). Stimulation with recombinant IL-33 did not affect the proliferation of CD8⁺ T cells or the expression of immune checkpoint molecules (P > 0.05), but it promoted the secretion of perforin and granzyme B (P < 0.05). Compared with the control group, the HCC group had a significant reduction in the killing activity of CD8⁺ T cells (P < 0.05), and stimulation with recombinant IL-33 enhanced the killing function of CD8⁺ T cells, which was mainly reflected in the increases in the proportion of dead HepG2 cells (P < 0.05) and the secretion of IFNγ and TNFα (P < 0.05). Conclusion There is a reduction in the plasma level of IL-33 in HCC patients. IL-33 can enhance the killing activity of CD8⁺ T cells by promoting the secretion of perforin and granzyme B, which provides a new target for the treatment of HCC.
- Carcinoma, Hepatocellular,
- Interleukin-33,
- CD8-Positive T-Lymphocytes

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References

[1]	CHEN Y, TIAN Z. HBV-induced immune imbalance in the development of HCC[J]. Front Immunol, 2019, 10: 2048. DOI: 10.3389/fimmu.2019.02048.
[2]	HOFMANN M, TAUBER C, HENSEL N, et al. CD8⁺ T cell responses during HCV infection and HCC[J]. J Clin Med, 2021, 10(5): 991. DOI: 10.3390/jcm10050991.
[3]	CAYROL C, GIRARD JP. Interleukin-33?(IL-33): A nuclear cytokine from the IL-1 family[J]. Immunol Rev, 2018, 281(1): 154-168. DOI: 10.1111/imr.12619.
[4]	JIN Z, LEI L, LIN D, et al. IL-33 released in the liver inhibits tumor growth via promotion of CD4(+) and CD8(+) T cell responses in hepatocellular carcinoma[J]. J Immunol, 2018, 201(12): 3770-3779. DOI: 10.4049/jimmunol.1800627.
[5]	LI A, HERBST RH, CANNER D, et al. IL-33 signaling alters regulatory T cell diversity in support of tumor development[J]. Cell Rep, 2019, 29(10): 2998-3008. e8. DOI: 10.1016/j.celrep.2019.10.120.
[6]	Bureau of Medical Administrationnational Health Commission of The People's Republic of China. Guidelines for diagnosis and treatment of primary liver cancer in China (2019 edition)[J]. J Clin Hepatol, 2020, 36(2): 277-292. DOI: 10.3969/j.issn.1001-5256.2020.02.007. 中华人民共和国国家卫生健康委员会医政医管局. 原发性肝癌诊疗规范(2019年版)[J]. 临床肝胆病杂志, 2020, 36(2): 277-292. DOI: 10.3969/j.issn.1001-5256.2020.02.007.
[7]	BOEGEL S, LÖWER M, BUKUR T, et al. A catalog of HLA type, HLA expression, and neo-epitope candidates in human cancer cell lines[J]. Oncoimmunology, 2014, 3(8): e954893. DOI: 10.4161/21624011.2014.954893.
[8]	LI PP, ZHANG XM, YUAN D, et al. Decreased expression of IL-33 in immune thrombocytopenia[J]. Int Immunopharmacol, 2015, 28(1): 420-424. DOI: 10.1016/j.intimp.2015.06.035.
[9]	XU H, TURNQUIST HR, HOFFMAN R, et al. Role of the IL-33-ST2 axis in sepsis[J]. Mil Med Res, 2017, 4: 3. DOI: 10.1186/s40779-017-0115-8.
[10]	LU Y. Correlation of serum interleukin-33 with HBV DNA load and ALT level in patients with chronic hepatitis B[J]. J Clin Hepatol, 2015, 31(11): 1853-1856. DOI: 10.3969/j.issn.1001-5256.2015.11.020. 陆盈. 慢性乙型肝炎患者血清白细胞介素33与HBV DNA及ALT水平的相关性分析[J]. 临床肝胆病杂志, 2015, 31(11): 1853-1856. DOI: 10.3969/j.issn.1001-5256.2015.11.020.
[11]	ANTUNES MM, ARAÚJO AM, DINIZ AB, et al. IL-33 signalling in liver immune cells enhances drug-induced liver injury and inflammation[J]. Inflamm Res, 2018, 67(1): 77-88. DOI: 10.1007/s00011-017-1098-3.
[12]	YAZDANI HO, CHEN HW, TOHME S, et al. IL-33 exacerbates liver sterile inflammation by amplifying neutrophil extracellular trap formation[J]. J Hepatol, 2017. DOI: 10.1016/j.jhep.2017.09.010.[Onlineaheadofprint]
[13]	DU XX, SHI Y, YANG Y, et al. DAMP molecular IL-33 augments monocytic inflammatory storm in hepatitis B-precipitated acute-on-chronic liver failure[J]. Liver Int, 2018, 38(2): 229-238. DOI: 10.1111/liv.13503.
[14]	KHAN HA, MUNIR T, KHAN JA, et al. IL-33 ameliorates liver injury and inflammation in Poly Ⅰ∶ C and Concanavalin-A induced acute hepatitis[J]. Microb Pathog, 2021, 150: 104716. DOI: 10.1016/j.micpath.2020.104716.
[15]	YANG Y, WANG JB, LI YM, et al. Role of IL-33 expression in oncogenesis and development of human hepatocellular carcinoma[J]. Oncol Lett, 2016, 12(1): 429-436. DOI: 10.3892/ol.2016.4622.
[16]	PENG C, HAN J, YE X, et al. IL-33 Treatment attenuates the systemic inflammation reaction in acinetobacter baumannii pneumonia by suppressing TLR4/NF-κB signaling[J]. Inflammation, 2018, 41(3): 870-877. DOI: 10.1007/s10753-018-0741-7.
[17]	LV R, ZHAO J, LEI M, et al. IL-33 Attenuates sepsis by inhibiting IL-17 receptor signaling through upregulation of SOCS3[J]. Cell Physiol Biochem, 2017, 42(5): 1961-1972. DOI: 10.1159/000479836.
[18]	BAO Q, LV R, LEI M. IL-33 attenuates mortality by promoting IFN-γ production in sepsis[J]. Inflamm Res, 2018, 67(6): 531-538. DOI: 10.1007/s00011-018-1144-9.
[19]	ALVES-FILHO JC, SȎNEGO F, SOUTO FO, et al. Interleukin-33 attenuates sepsis by enhancing neutrophil influx to the site of infection[J]. Nat Med, 2010, 16(6): 708-712. DOI: 10.1038/nm.2156.
[20]	NASCIMENTO DC, MELO PH, PIÑEROS AR, et al. IL-33 contributes to sepsis-induced long-term immunosuppression by expanding the regulatory T cell population[J]. Nat Commun, 2017, 8: 14919. DOI: 10.1038/ncomms14919.
[21]	XIA Y, OHNO T, NISHⅡ N, et al. Endogenous IL-33 exerts CD8(+) T cell antitumor responses overcoming pro-tumor effects by regulatory T cells in a colon carcinoma model[J]. Biochem Biophys Res Commun, 2019, 518(2): 331-336. DOI: 10.1016/j.bbrc.2019.08.058.
[22]	DREIS C, OTTENLINGER FM, PUTYRSKI M, et al. Tissue cytokine IL-33 modulates the cytotoxi CD8 T lymphocyte activity during nutrient deprivation by regulation of lineage-specific differentiation programs[J]. Front Immunol, 2019, 10: 1698. DOI: 10.3389/fimmu.2019.01698.
[23]	ROOD JE, BURN TN, NEAL V, et al. Disruption of IL-33 signaling limits early CD8⁺ T cell effector function leading to exhaustion in murine hemophagocytic lymphohistiocytosis[J]. Front Immunol, 2018, 9: 2642. DOI: 10.3389/fimmu.2018.02642.
[24]	WANG W, WU J, JI M, et al. Exogenous interleukin-33 promotes hepatocellular carcinoma growth by remodelling the tumour microenvironment[J]. J Transl Med, 2020, 18(1): 477. DOI: 10.1186/s12967-020-02661-w.
[25]	ZHAO R, YU Z, LI M, et al. Interleukin-33/ST2 signaling promotes hepatocellular carcinoma cell stemness expansion through activating c-Jun N-terminal kinase pathway[J]. Am J Med Sci, 2019, 358(4): 279-288. DOI: 10.1016/j.amjms.2019.07.008.

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Expression of interleukin-33 in hepatocellular carcinoma patients and its role in regulating CD8⁺ T cell function

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Expression of interleukin-33 in hepatocellular carcinoma patients and its role in regulating CD8+ T cell function

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Expression of interleukin-33 in hepatocellular carcinoma patients and its role in regulating CD8⁺ T cell function