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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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