Identification of an Immune-specific Class of Hepatocellular Carcinoma, Based on Molecular Features

Abstract

In an analysis of HCC samples from 956 patients, we found almost 25% to express markers of an inflammatory response. We identified 2 subclasses, characterized by adaptive or exhausted immune responses. These findings indicate that some HCCs might be susceptible to therapeutic agents designed to block the regulatory pathways in T cells, such as programmed death-ligand 1, programmed cell death 1, or transforming growth factor beta 1 inhibitors.

Landscape of immune microenvironment in hepatocellular carcinoma and its additional impact on histological and molecular classification

“…Hierarchical cluster analysis showed regions with high expression of Th1/CTL‐related mRNA (especially Ifng, Gzmb, Cxcl9 , and Cxcl10 ; Fig. A), which was very similar to the previously defined “Immune class” signature in HCC . Expression of Th17‐related mRNA was relatively low, which is compatible with a previous study showing a lower frequency of Th17 cells among tumor‐infiltrating lymphocytes in HCC .…”

Immune Gene Expression Profile in Hepatocellular Carcinoma and Surrounding Tissue Predicts Time to Tumor Recurrence

“…Previous reports have identified immune-related gene signatures in HCC and/or the surrounding liver by microarray profiling [23-28]. In HCC tissue, an interferon (IFN)-related molecular subclass has been associated with increased leukocyte infiltration and tumor apoptosis [23] and with smaller tumor size [25].…”

“…An immune gene profile predictive of patient survival included the chemokine genes CXCL10, CCL5, and CCL2, whose expression correlated with tumor infiltration by CD8+ T cells, NK cells, and Th1 cells [29, 30]. Sia et al [28] identified markers of inflammatory response in about 25% of HCCs with evidence of two distinct immune subtypes, characterized by a prevalent adaptive T-cell response and an exhausted immune response, respectively. Interestingly, the patients with an active immune response showed a longer median TTR, consistent with the results of the present study.…”

“…The expression profile derived from nontumorous liver tissue was mostly related to late recurrence occurring more than 2 years after surgery, possibly including the development of de novo tumors arising in cirrhotic tissue [27]. In a recent study, the immune-enriched gene expression signature of nontumorous liver tissue did not reflect the profile of matched tumors, and was associated with shorter survival [28]. Our results are in line with these observations and with our previous study [31], supporting the view that an inflammatory milieu in surrounding liver tissue is related to worse prognosis.…”

Development of a PD-L1-Expressing Orthotopic Liver Cancer Model: Implications for Immunotherapy for Hepatocellular Carcinoma

“…This model was characterized by SDF-1α/C-X-C receptor type 4 (CXCR4)-dependent infiltration of myeloid cells in the tumor microenvironment, which may offset the potential antitumor synergy between anti-PD1 and sorafenib or other targeted agents. A recent transcriptomic study of the immune characteristics of HCC tumors and the surrounding liver indicated that the immune contexture of the surrounding liver was mostly immunosuppressive and associated with inferior survival of HCC patients [44]. Prospective biomarker studies within the context of drug clinical trials are necessary to clarify whether the inflammatory microenvironment in HCC patients with underlying cirrhosis may negate the immunomodulatory effects of antiangiogenic agents.…”