Immunological Microenvironment of Hepatocellular Carcinoma and Its Clinical Implication

Abstract

Despite recent advances in the treatment of hepatocellular carcinoma (HCC), the prognosis of patients with advanced stage of disease remains unfavorable. Several immune therapies have been applied to HCC, and their responses have not been satisfactory. The immune response to cancer is determined by the balance between the antigenicity of the tumor and the microenvironment of cancer tissues. Generally, accumulated genetic mutations are observed in HCC, which may lead to increased neoantigens on cancer cells with high antigenicity. However, cancer cells may evade the immune system because of alterations in molecules and cellular pathways involved in antigen processing and presentation. In addition, hypoxia in tissue induces several cytokines, chemokines, and immunosuppressive molecules from HCC cells and stromal cells. These cells also produce cytokines that attract regulatory T cells infiltrating tumor tissues and contribute to establishing an immunosuppressive microenvironment. Some cancers show a good response to immune checkpoint therapy. However, prolonged stabilization of disease for this treatment is reportedly 12-41% in patients with advanced cancer. Therefore, immunosuppressive forces in the microenvironment of HCC may cause resistance to immune therapy, and modification of the tumor microenvironment may restore normal anticancer immunity. In this review, we focus on the immunological microenvironment of HCC tissues and discuss how the immunosuppressive environment of HCC should be modulated to achieve a favorable response to immune therapy, such as immune checkpoint therapy, in HCC.

Clinicopathologic and prognostic significance of regulatory T cells in patients with hepatocellular carcinoma: a meta-analysis

“…The liver is considered a immune organ and immune escape is one of the mechanisms of hepatocarcinogenesis [4, 5]. The immunological microenvironment is very important for progression of HCC and regulatory T cells (Tregs) are in involved in the immunological microenvironment [6]. …”

Oncogenic Signal and Tumor Microenvironment in Hepatocellular Carcinoma

“…cellular signals activated through genetic and epigenetic alterations could induce the production of immunosuppressive molecules in HCC tissues [8] . In this review, we focus on the establishment of immunosuppressive microen vironment in the context of activation of oncogenic signaling.…”

Role of Immune Checkpoint Blockade in the Treatment for Human Hepatocellular Carcinoma

“…In the HCC microenvironment, immunosuppressive cytokines, chemokines, and stromal cells could counter the effects of immune checkpoint inhibitors [29] . For example, a high IL-6 expression in cancer-associated fibroblasts reportedly can lead to both the recruitment of immunosuppressive myeloid-derived cells and the induction of immune checkpoints molecules, which in turn could 621 result in the establishment of an immunosuppressive microenvironment [30] .…”