The Role of Immunotherapy in a Tolerogenic Environment: Current and Future Perspectives for Hepatocellular Carcinoma

Abstract

In contrast to several tumors whose prognoses are radically affected by novel immunotherapeutic approaches and/or targeted therapies, the outcomes of advanced hepatocellular carcinoma (HCC) remain poor. The underlying cirrhosis that is frequently associated with it complicates medical treatment and often determines survival. The landscape of HCC treatment had included sorafenib as the only drug available for ten years, until 2018, when lenvatinib was approved for treatment. The second-line systemic treatments available for hepatocellular carcinoma include regorafenib, cabozantinib, ramucirumab, and, more recently, immune checkpoint inhibitors. However, the median survival remains below 15 months. The results obtained in clinics should be interpreted whilst considering the peculiar role of the liver as an immune organ. A healthy liver microenvironment ordinarily experiences stimulation by gut-derived antigens. This setup elucidates the response to chronic inflammation and the altered balance between tolerance and immune response in HCC development. This paper provides an overview of the mechanisms involved in HCC pathogenesis, with a special focus on the immune implications, along with current and future clinical perspectives.

NK cell marker gene-based model shows good predictive ability in prognosis and response to immunotherapies in hepatocellular carcinoma

“…With the difficulties of early diagnosis and insufficient efficacy of advanced-stage therapies, the main obstacles for cancer management are exploring novel diagnostic biomarkers for early diagnosis and improving therapy effectiveness and prognosis prediction 16 . The liver is the largest immune organ that has typical immune tolerance characteristics 17 . HCC has become the leading cause of cancer-related deaths in the world 18 .…”

Hepatocellular Carcinoma Subtyping and Prognostic Model Construction Based on Chemokine-Related Genes

“…Immunotherapy is gradually emerging as an approach for cancer treatment, with PD1/PDL1 antibodies being the most studied and applied in malignant tumors such as melanoma, pancreatic, liver, and non-small cell lung cancers [20][21][22][23]. Nevertheless, different immune cells play different roles in the immune microenvironment of liver cancer [24], and owing to the intricate nature of the immune environment and the restrictions of existing immunotherapies, significant gaps remain in our understanding of immunotherapy. Developing effective immunotherapy for HCC patients remains a major challenge.…”

Personalized treatment for hepatocellular carcinoma: Current status and future perspectives

“…Third, over 90% of HCC occur as the consequence of long process of chronic hepatic inflammation and cirrhotic damage 13 . It is evident that the non‐tumoral microenvironment in the liver or in the systemic circulation also contributes significantly to the proliferation of HCC 13,14 . To purse precision or even personalized medicine in HCC, the environment of tumor also needs to be considered and targeted.…”

“…13 It is evident that the non-tumoral microenvironment in the liver or in the systemic circulation also contributes significantly to the proliferation of HCC. 13,14 To purse precision or even personalized medicine in HCC, the environment of tumor also needs to be considered and targeted. In summary, above obstacles have slowed down the progress of development.…”