Revised Immunogenomic Classification of Liver Cancer May Help Predict Immunotherapy Response

NEW YORK (Reuters Health) – A revised immunogenomic classification for hepatocellular carcinoma (HCC) includes several novel mechanisms of immune response and evasion and may help to better gauge outcome associated with immunotherapy in HCC, the developers say.

The advent of immune-checkpoint inhibitors (ICIs) has transformed the field of immune-oncology and revolutionized the management of cancer. In HCC, however, only about one in five patients mount a durable response.

A recent study found significant differences in clinical outcomes following ICI therapy based on underlying liver-disease etiology, with a much greater benefit in viral-related than in non-viral-related HCC.

In earlier work, Dr. Josep Llovet with the Tisch Cancer Institute at Mount Sinai in New York and colleagues identified an immune-specific class of HCC present in roughly a quarter of patients with HCC ( However, the immune traits of the remaining three-quarters of HCCs are not well defined.

Using an integrative genomic approach, the researchers refined the inflamed class, which makes up 37% of HCC patients and includes the previously reported immune subclass (22%) and a new immune-like subclass (15%) characterized by high interferon signaling, cytolytic activity, expression of immune-effector cytokines and a more diverse T-cell repertoire.

Of note, they say a 20-gene signature captures roughly 90% of HCC in the inflamed class, is associated with response to immunotherapy and can be tested as a direct biomarker of response.

“Importantly, these inflamed HCC tumors were enriched in two recently reported inflammatory signatures predicting ICI response in advanced HCC patients and was enriched in responders to ICIs in a small published cohort,” the researchers note in their paper in Gut.

Non-inflamed HCC, which makes up roughly 63% of cases, depicts immune features that are significantly distinct from the inflamed class and fall into two distinct classes based on the underlying mechanisms of immune evasion: the intermediate and the excluded class.

The intermediate class is enriched in TP53 mutations and chromosomal losses involving immune-related genes and the excluded class is enriched in CTNNB1 mutations and PTK2 over-expression due to gene amplification and promoter hypomethylation.

Dr. Llovet and colleagues have proposed a diagnostic algorithm to help implement this classification in clinical practice to further evaluate the predictive potential of the inflamed class in ICI-treated HCC cohorts.

This research was partially funded by a grant from Bristol-Myers Squibb. Several authors have disclosed relationships with the company and other pharmaceutical companies.

SOURCE: Gut, online March 2, 2022.

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