The Tumor Microenvironment of Hepatocellular Carcinoma: Untying an Intricate Immunological Network

Abstract

HCC, the most prevalent form of primary liver cancer, is prototypically an inflammation-driven cancer developing after years of inflammatory insults. Consequently, the hepatic microenvironment is a site of complex immunological activities. Moreover, the tolerogenic nature of the liver can act as a barrier to anti-tumor immunity, fostering cancer progression and resistance to immunotherapies based on immune checkpoint inhibitors (ICB). In addition to being a site of primary carcinogenesis, many cancer types have high tropism for the liver, and patients diagnosed with liver metastasis have a dismal prognosis. Therefore, understanding the immunological networks characterizing the tumor microenvironment (TME) of HCC will deepen our understanding of liver immunity, and it will underpin the dominant mechanisms controlling both spontaneous and therapy-induced anti-tumor immune responses. Herein, we discuss the contributions of the cellular and molecular components of the liver immune contexture during HCC onset and progression by underscoring how the balance between antagonistic immune responses can recast the properties of the TME and the response to ICB.

Cellular Senescence in Liver Cancer: How Dying Cells Become “Zombie” Enemies

“…The liver is a central organ performing vital functions related to the metabolism of nutrients, toxins, and drugs, as well as digestion and immunity. Because of its anatomy, the portal circulation constantly exposes the liver to a significant number of foreign molecules including pathogens [99]. The portal vein drains blood from the intestine, spleen, and pancreas to the liver, carrying many foreign molecules derived from both food and the intestinal microbiota.…”

“…Additionally, ICB treatments have been associated with immune-related hepatotoxicity and poorer outcomes in some HCC patients [107]. Indeed, the liver possesses a complex immunological network that creates a delicate balance between tolerance toward harmless antigens and activation against potential pathogens [99]. HCC usually develops in the context of chronic inflammation and cirrhosis, a primary cause of immune exhaustion that, in turn, enhances the liver's immunosuppressive status.…”

Antitumor immunostimulatory activity of the traditional Chinese medicine polysaccharide on hepatocellular carcinoma

“…The immune system has the functions of immune surveillance, defense, and regulation, and is composed of immune organs, immune cells, and immune active substances. The reason why tumors can escape the immune surveillance of the body is principally because they can produce excessive immunosuppressive factors, resulting in poor antitumor immune function in patients, which is not enough to produce a strong antitumor immune response to clear tumor cells ( 8 – 10 ). Therefore, the immunosuppressive microenvironment of HCC can provide a favorable condition for tumor growth, and immunotherapy is one of the effective methods to inhibit HCC growth ( 11 ).…”

Hepatocellular carcinoma (HCC) tumor microenvironment is more suppressive than colorectal cancer liver metastasis (CRLM) tumor microenvironment

“…Inflammation triggers the de-differentiation of liver cells into tumorigenic stem-like cells. These phenomena explain the intra- and intertumor heterogeneity existing among different types of HCC and are associated with tumor microenvironment (TME) evolution toward increasing immunosuppressive phenotype [ 5 ]. Lesions in the same tumor may have distinctive genomic alterations, biological behaviors and local microenvironments and can respond differently to therapies, but the immune status of the HCC microenvironment was relatively less heterogenous recognizing three distinctive HCC-TME subtypes (immunocompetent, immunodeficient and immunosuppressive) strongly dependent on T regulatory cells (Tregs) infiltration [ 6 ].…”