Immune Phenotype and Immune Checkpoint Inhibitors for the Treatment of Human Hepatocellular Carcinoma

Abstract

Immunotherapies are promising approaches for treating hepatocellular carcinomas (HCCs) refractory to conventional therapies. However, a recent clinical trial of immune checkpoint inhibitors (ICIs) revealed that anti-tumor responses to ICIs are not satisfactory in HCC cases. Therefore, it is critical to identify molecular markers to predict outcome and develop novel combination therapies that enhance the efficacy of ICIs. Recently, several attempts have been made to classify HCC based on genome, epigenome, and transcriptome analyses. These molecular classifications are characterized by unique clinical and histological features of HCC, as well immune phenotype. For example, HCCs exhibiting gene expression patterns with proliferation signals and stem cell markers are associated with the enrichment of immune infiltrates in tumors, suggesting immune-proficient characteristics for this type of HCC. However, the presence of activating mutations in β-catenin represents a lack of immune infiltrates and refractoriness to ICIs. Although the precise mechanism that links the immunological phenotype with molecular features remains controversial, it is conceivable that alterations of oncogenic cellular signaling in cancer may lead to the expression of immune-regulatory molecules and result in the acquisition of specific immunological microenvironments for each case of HCC. Therefore, these molecular and immune characteristics should be considered for the management of HCC using immunotherapy.

Immune checkpoint molecules are regulated by transforming growth factor (TGF)-β1-induced epithelial-to-mesenchymal transition in hepatocellular carcinoma

“…Several ICI drugs targeting CTLA-4 or PD-1/PD-L1 interaction have been approved by the FDA for various cancer types including melanoma, lung cancer, renal cell carcinoma, breast cancer, head and neck cancer, colorectal cancer, urothelial cancer and HCC [18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33]. Despite the approval of few ICIs and several ongoing clinical trials, ICIs as a monotherapy have failed to show promising result as first-line treatment in HCC compared to Sorafenib [53,54]. In addition, the response of HCC patients to ICIs may be affected by several molecular features including genetic alterations, variation in inflammatory infiltrates, microsatellite instability (MSI) and expression of alternative immune checkpoint molecules [53,55,56].…”

“…Despite the approval of few ICIs and several ongoing clinical trials, ICIs as a monotherapy have failed to show promising result as first-line treatment in HCC compared to Sorafenib 53 , 54 . In addition, the response of HCC patients to ICIs may be affected by several molecular features including genetic alterations, variation in inflammatory infiltrates, microsatellite instability (MSI) and expression of alternative immune checkpoint molecules 53 , 55 , 56 . Thus, there is a need for identification of robust predictive biomarkers along with combined ICI therapeutic approaches for enhanced clinical outcome in HCC patients 53 .…”

Progress and Challenges of Predictive Biomarkers for Immune Checkpoint Blockade

“…Furthermore, CTNNB1 status might have a potential to predict patients' response to anti-PD-1 therapy. CTNNB1 is one of the frequently mutated genes in HCC and has been related to alcohol intake ( 64 , 65 ). It has also been found to be associated with tumor classifications as well as tumor characteristics.…”

“…It has also been found to be associated with tumor classifications as well as tumor characteristics. In general, HCC with CTNNB1 mutations show microtrabecular or pseudoglandular histological patterns, cholestatic tendencies, and T cell exclusion ( 65 ). Harding et al implemented prospective NGS in the patients and found that CTNNB1-mutated HCC was associated with innate resistance to immune checkpoint inhibitors ( 66 ).…”

Long-term prognosis and management of hepatocellular carcinoma after curative treatment

“…17,18 Contentious induction of interferon-γ could induce immune checkpoint molecules, and recruitment of regulatory T cell, polarization of macrophages to immune suppressive M2 phenotype during healing process, and shifting the balance of helper T cell to immunosuppressive T-helper 2 phenotype occur during the progression of chronic inflammations. 19,20 Collectively, these processes can contribute to the high recurrence rate of HCC after curative treatments compared to other cancers.…”