Hepatocellular carcinoma in viral and autoimmune liver diseases: Role of CD4+ CD25+ Foxp3+ regulatory T cells in the immune microenvironment

Abstract

More than 90% of cases of hepatocellular carcinoma (HCC) occurs in patients with cirrhosis, of which hepatitis B virus and hepatitis C virus are the leading causes, while the tumor less frequently arises in autoimmune liver diseases. Advances in understanding tumor immunity have led to a major shift in the treatment of HCC, with the emergence of immunotherapy where therapeutic agents are used to target immune cells rather than cancer cells. Regulatory T cells (Tregs) are the most abundant suppressive cells in the tumor microenvironment and their presence has been correlated with tumor progression, invasiveness, as well as metastasis. Tregs are characterized by the expression of the transcription factor Foxp3 and various mechanisms ranging from cell-to-cell contact to secretion of inhibitory molecules have been implicated in their function. Notably, Tregs amply express checkpoint molecules such as cytotoxic T lymphocyte-associated antigen 4 and programmed cell-death 1 receptor and therefore represent a direct target of immune checkpoint inhibitor (ICI) immunotherapy. Taking into consideration the critical role of Tregs in maintenance of immune homeostasis as well as avoidance of autoimmunity, it is plausible that targeting of Tregs by ICI immunotherapy results in the development of immune-related adverse events (irAEs). Since the use of ICI becomes common in oncology, with an increasing number of new ICI currently under clinical trials for cancer treatment, the occurrence of irAEs is expected to dramatically rise. Herein, we review the current literature focusing on the role of Tregs in HCC evolution taking into account their opposite etiological function in viral and autoimmune chronic liver disease, and we discuss their involvement in irAEs due to the new immunotherapies.

Immune Responses Following Locoregional Treatment for Hepatocellular Carcinoma: Possible Roles of Adjuvant Immunotherapy

“…In addition to chronic antigenic stimulation and exhaustion of CD8 + T cells, other immune cells contribute to weak anti-tumor CD8 + T cell responses in HCC. CD4 + CD25 + FoxP3 + regulatory T (Treg) cells exhibit on their surface both CTLA-4 and PD-1 and can be a target cell population of ICBs [ 31 ]. They are increased in the HCC microenvironment and impair CD8 + T cell-responses [ 32 , 33 ].…”

The Effect of Ferroptosis-Related Genes on Prognosis and Tumor Mutational Burden in Hepatocellular Carcinoma

“…Hepatocellular carcinoma (HCC) is a liver tumor with a poor prognosis. It is the sixth most common malignancy worldwide [ 1 ], which occurs most often in those with chronic liver diseases such as cirrhosis caused by hepatitis C or B infection, primary biliary cholangitis or alcoholic hepatitis, metabolic disorders, and ingestion of aflatoxin-contaminated food that are all considered as risk factors contributing to the development of HCC [ 2 – 4 ]. Surgery and liver transplantation, followed by chemotherapy and radiotherapy, are considered as the main treatment approaches; the treatment is usually based on the tumor stage and size.…”

Clinical Significance and Integrative Analysis of the SMC Family in Hepatocellular Carcinoma

“…Among them, M2 cells play a positive role in the occurrence and development of cancer ( 43 ). Moreover, CD4+ CD25+ FOXP3 regulatory T cells (TREG) is one of the most studied cell population in the study of tumor microenvironment, which displayed the immunosuppressive role and could be a target of immunotherapy in the HCC ( 44 ). However, due to the limitation of TIMER database, we didn't analyze the correlation between the expression of SMC family genes and TREG infiltration in HCC, and will further explore their relationship in the subsequent study.…”