From bench to bed: the tumor immune microenvironment and current immunotherapeutic strategies for hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) ranks the most common primary liver malignancy and the third leading cause of tumor-related mortality worldwide. Unfortunately, despite advances in HCC treatment, less than 40% of HCC patients are eligible for potentially curative therapies. Recently, cancer immunotherapy has emerged as one of the most promising approaches for cancer treatment. It has been proven therapeutically effective in many types of solid tumors, such as non-small cell lung cancer and melanoma. As an inflammation-associated tumor, it’s well-evidenced that the immunosuppressive microenvironment of HCC can promote immune tolerance and evasion by various mechanisms. Triggering more vigorous HCC-specific immune response represents a novel strategy for its management. Pre-clinical and clinical investigations have revealed that various immunotherapies might extend current options for needed HCC treatment. In this review, we provide the recent progress on HCC immunology from both basic and clinical perspectives, and discuss potential advances and challenges of immunotherapy in HCC.

Eight-Gene Metabolic Signature Related with Tumor-Associated Macrophages Predicting Overall Survival for Hepatocellular Carcinoma

“…Hepatocellular carcinoma(HCC) acts as a representative primary liver cancer. Despite the improved treatment recently, its still holds a low ve-year survival [23]. The mechanism of occurrence and development of HCC remains to be further clari ed.…”

The Crosstalk between Tumor Cells and the Microenvironment in Hepatocellular Carcinoma: The Role of Exosomal microRNAs and Their Clinical Implications

“…The different tumor-infiltrating lymphocyte (TIL) subtypes have an opposite role within the TME. Both CD8+ cytotoxic T cells (CD8+CD45RO+) and CD4+ T helper 1 (Th1) cells exert an antitumor activity, and thus their presence is associated to good prognosis [7,9]. On the contrary, CD4+ TH2, producing IL-4, IL-5, and IL-13, generally promote tumor growth and development [9].…”

“…Both CD8+ cytotoxic T cells (CD8+CD45RO+) and CD4+ T helper 1 (Th1) cells exert an antitumor activity, and thus their presence is associated to good prognosis [7,9]. On the contrary, CD4+ TH2, producing IL-4, IL-5, and IL-13, generally promote tumor growth and development [9]. The CD4+ regulatory T cells (Tregs) are characterized by the expression of Forkhead Box P3(FOXP3) and CD25+ and are commonly described as tumor-promoting TILs.…”

Gene Therapy for Liver Cancers: Current Status from Basic to Clinics

“…However, these MTAs also have limitations owing to the heterogeneity of HCC, and signaling pathway-specific inhibitors, such as those inhibiting fibroblast growth factor (FGF) 19-FGFR4 signaling pathways, are used in clinical trials [13]. Immune checkpoint inhibitors have also been tested [14], but have shown low efficacy in HCC as a current strategy, and further modification of the immune environment is essential [15][16][17]. Overall, HCC is characterized by heterogeneity [18][19][20][21], high risk of recurrence, and drug resistance.…”

“…At the basic level, other pro-apoptotic genes, such as Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), have been tested to induce apoptosis in HCC cells. Adeno-associated virus (AAV)-human telomerase reverse transcriptase (hTERT)-TRAIL displayed cancer-specific cytotoxicity, and intratumoral administration of AAV-hTERT-TRAIL significantly suppressed tumor growth in a xenograft model [15,49,50].…”