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转化生长因子-β1通过增强肝癌T淋巴细胞上PD-1和CTLA-4的表达诱导免疫逃逸。

TGF-β1 Induces Immune Escape by Enhancing PD-1 and CTLA-4 Expression on T Lymphocytes in Hepatocellular Carcinoma.

作者信息

Bao Shixiang, Jiang Xiaopei, Jin Shuai, Tu Peipei, Lu Jingtao

机构信息

School of Life Sciences, Anhui Medical University, Hefei, China.

出版信息

Front Oncol. 2021 Jun 25;11:694145. doi: 10.3389/fonc.2021.694145. eCollection 2021.

Abstract

Primary liver cancer (PLC) is one of the most common types of cancer worldwide. Hepatocellular carcinoma (HCC) accounts for approximately 90% of PLC cases. The HCC microenvironment plays an important role in the occurrence and development of HCC. Immunotherapy for the HCC microenvironment has become an effective treatment strategy. T lymphocytes are an important part of the HCC microenvironment, and programmed cell death 1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) are the main immunosuppressive molecules of T lymphocytes. Transforming growth factor β1 (TGF-β1) can inhibit the immune function of T lymphocytes and promote the occurrence and development of tumors. However, few studies have explored whether TGF-β1 can upregulate the expression of PD-1 and CTLA-4 on T cells. In this study, we showed that TGF-β1 upregulated the expression of PD-1 and CTLA-4 on T lymphocytes and attenuated the cytotoxicity of T lymphocytes for HCC cells and . In addition, TGF-β1 increased the apoptosis of T lymphocytes induced by HCC cells. Finally, we found that the mechanism by which TGF-β1 upregulates the expression of PD-1 and CTLA-4 on T lymphocytes may be related to the calcineurin-nuclear factor of activated T cells 1 (CaN/NFATc1) pathway. This study will provide some experimental basis for liver cancer immunotherapy based on the tumor microenvironment.

摘要

原发性肝癌(PLC)是全球最常见的癌症类型之一。肝细胞癌(HCC)约占PLC病例的90%。HCC微环境在HCC的发生和发展中起重要作用。针对HCC微环境的免疫疗法已成为一种有效的治疗策略。T淋巴细胞是HCC微环境的重要组成部分,程序性细胞死亡蛋白1(PD-1)和细胞毒性T淋巴细胞相关抗原4(CTLA-4)是T淋巴细胞的主要免疫抑制分子。转化生长因子β1(TGF-β1)可抑制T淋巴细胞的免疫功能,促进肿瘤的发生和发展。然而,很少有研究探讨TGF-β1是否能上调T细胞上PD-1和CTLA-4的表达。在本研究中,我们发现TGF-β1上调了T淋巴细胞上PD-1和CTLA-4的表达,并减弱了T淋巴细胞对HCC细胞的细胞毒性。此外,TGF-β1增加了HCC细胞诱导的T淋巴细胞凋亡。最后,我们发现TGF-β1上调T淋巴细胞上PD-1和CTLA-4表达的机制可能与钙调神经磷酸酶-活化T细胞核因子1(CaN/NFATc1)途径有关。本研究将为基于肿瘤微环境的肝癌免疫治疗提供一些实验依据。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a445/8270637/9f333cf27cdf/fonc-11-694145-g001.jpg

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