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 in vitro and in vivo. 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.
Highlights
Hepatocellular carcinoma (HCC) is the sixth most common type of human cancer and the secondleading cause of cancer-related death worldwide [1]
The results of flow cytometry (Figure 1A) and Western blot (Figure 1B) showed that Transforming growth factor b1 (TGF-b1) significantly enhanced the expression of Programmed cell death 1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) on T cells
We found that TGF-b1 upregulated the expression of PD-1 and CTLA-4 in a concentration-dependent manner (Figure 1)
Summary
Hepatocellular carcinoma (HCC) is the sixth most common type of human cancer and the secondleading cause of cancer-related death worldwide [1]. PD-L1 is the main ligand of PD-1, and its expression is enhanced in a variety of solid tumors It mainly plays a role in weakening the function of local tumor-infiltrating T lymphocytes and reducing the production of killer cytokines. Following the binding of PD-1 to PD-L1, it provides stimulation signals for inhibiting the proliferation of activated T cells [7]. It inhibits the secretion of cytokines interleukin-1 (IL-1) and IL-2, promotes T cell apoptosis, mediates tumor immune escape, and promotes tumor growth [8,9,10]. The pathway plays an important role in mediating the immune escape of HCC
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