Inflamed and non-inflamed classes of HCC: a revised immunogenomic classification

Abstract

ObjectiveWe previously reported a characterisation of the hepatocellular carcinoma (HCC) immune contexture and described an immune-specific class. We now aim to further delineate the immunogenomic classification of HCC to incorporate features that explain responses/resistance to immunotherapy.DesignWe performed RNA and whole-exome sequencing, T-cell receptor (TCR)-sequencing, multiplex immunofluorescence and immunohistochemistry in a novel cohort of 240 HCC patients and validated our results in other cohorts comprising 660 patients.ResultsOur integrative analysis led to define: (1) the inflamed class of HCC (37%), which includes the previously reported immune subclass (22%) and a new immune-like subclass (15%) with high interferon signalling, cytolytic activity, expression of immune-effector cytokines and a more diverse T-cell repertoire. A 20-gene signature was able to capture ~90% of these tumours and is associated with response to immunotherapy. Proteins identified in liquid biopsies recapitulated the inflamed class with an area under the ROC curve (AUC) of 0.91; (2) The intermediate class, enriched in TP53 mutations (49% vs 29%, p=0.035), and chromosomal losses involving immune-related genes and; (3) the excluded class, enriched in CTNNB1 mutations (93% vs 27%, p<0.001) and PTK2 overexpression due to gene amplification and promoter hypomethylation. CTNNB1 mutations outside the excluded class led to weak activation of the Wnt-βcatenin pathway or occurred in HCCs dominated by high interferon signalling and type I antigen presenting genes.ConclusionWe have characterised the immunogenomic contexture of HCC and defined inflamed and non-inflamed tumours. Two distinct CTNNB1 patterns associated with a differential role in immune evasion are described. These features may help predict immune response in HCC.

Combination Immunotherapy with Anti-PD-1/PD-L1 Antibody plus Anti-VEGF Antibody May Promote Cytotoxic T Lymphocyte Infiltration in Hepatocellular Carcinoma, Including in the Noninflamed Subclass

“…Meanwhile, HNF4α induces OATP1B3 expression, which is associated with iso-to-higher intensity in the hepatobiliary phase of Gd-EOB-DTPA MRI [21-23], while the other phenotype should be completely different and associated with positive findings in FDG-PET images. Although the former does not respond to immunotherapy, the latter does respond, and this is consistent with the findings of Montironi et al [1].…”

“…Different from previous reports in other solid tumors in which immune exclusion is usually caused by CTNNB1 mutation, in the immunogenomic classification proposed by Montironi et al [1], novel findings that there are 2 types of HCCs with CTNNB1 mutations: one is the immune excluded subclass in the noninflamed class and the other is the immune-like subclass in the inflamed class. Although it is unclear at present, hypermethylation and hypomethylation of MHC class 1-related genes may be involved in the immune-excluded subclass and the immune-like subclass, respectively.…”

“…1). Interestingly, although CTNNB1 mutation was usually known to cause immune exclusion in other cancer types, only HCCs with CTNNB1 mutations are found to be classified into two distinct types, which are novel findings [1]: one in which PTK2 is hypomethylated and MHC class 1-related genes are hypermethylated, which leads to impaired antigen-presenting ability, and one in which MHC class 1-related genes are hypomethylated, indicating that HCC with CTNNB1 mutations can be either inflamed or noninflamed tumors [1] (Fig. 1).…”

“…

The most recent immunogenomic classification of hepatocellular carcinoma (HCC) was published in 2022 [1]. According to this report, 65% of HCC cases are of the noninflamed class, while 35% are of the inflamed class, the latter of which potentially respond well to immune checkpoint inhibitors.

…”

Immunogenomic classification of hepatocellular carcinoma patients for immune check-point inhibitors therapy:cui bono?

“…Marcus Tullius Cicero, https://www.britannica.com/biography/Cicero) from these immune-based therapies can be a game-changer in HCC therapy. In a work published in Gut, Montironi et al performed a molecular phenotyping study to dissect the immunogenomic patterns to predict ICIs response 2. The first thorough immune classification of HCC was reported in 2017 by this same group, implementing a transcriptomic deconvolution approach 3.…”