Role of Oncogenic Pathways on the Cancer Immunosuppressive Microenvironment and Its Clinical Implications in Hepatocellular Carcinoma

SIMPLE SUMMARY: Hepatocellular carcinoma is known to become resistant to treatments easily by mutations in genes involved in the key cellular pathways targeted by current molecular targeted agents (MTAs). However, the immune checkpoint inhibitor (ICI) is a promising modality for cancer treatment, in which the cancer cells are made recognizable by the immune system. Blockade of the PD1/PDL1 proteins, which help cancers evade the immune system, is currently being tested in clinical trials in combination with MTAs. In this review, several cellular signaling pathways that can alter the immune processes within the tumor and can subsequently affect the patient’s response to ICIs are detailed. This review may help scientists and clinicians to better understand the molecular factors that can influence ICI-based therapy and will help in identifying suitable cases for this type of treatment. ABSTRACT: The tumor immune microenvironment, including hepatocellular carcinoma (HCC), is complex, consisting of crosstalk among tumor components such as the cancer cells, stromal cells and immune cells. It is conceivable that phenotypic changes in cancer cells by genetic and epigenetic alterations affect the cancer–stroma interaction and anti-cancer immunity through the expression of immune checkpoint molecules, growth factors, cytokines, chemokines and metabolites that may act on the immune system in tumors. Therefore, predicting the outcome of ICI therapy requires a thorough understanding of the oncogenic signaling pathways in cancer and how they affect tumor immune evasion. In this review, we have detailed how oncogenic signaling pathways can play a role in altering the condition of the cellular components of the tumor immune microenvironment such as tumor-associated macrophages, regulatory T cells and myeloid-derived suppressor cells. The RAS/MAPK, PI3K/Akt, Wnt/β-catenin and JAK/STAT pathways have all been implicated in anti-tumor immunity. We also found that factors that reflect the immune microenvironment of the tumor, including the status of oncogenic pathways such as the volume of tumor-infiltrating T cells, expression of the immune checkpoint protein PD-1 and its ligand PD-L1, and activation of the Wnt/β-catenin signaling pathway, predict a response to ICI therapy in HCC cases.