Nature: Stay away from non-alcoholic fatty liver, it is the driving factor of hepatocellular carcinoma and the destructive molecule of immunotherapy

Overview of non-alcoholic fatty liver diseaseNon-alcoholic fatty liver disease (NAFLD) is common worldwide, but the highest reported incidence is in South America (31%) and the Middle East (32%), followed by Asia (27%), the United States (24%) and Europe (23%) (Reference 1).

Non-alcoholic steatohepatitis (NASH) is a pathological phenotype of NAFLD, which may progress to advanced liver disease, cirrhosis and hepatocellular carcinoma (HCC).

The prevalence of NAFLD continues to increase (15% in 2005 to 25% in 2010).
Similarly, the incidence of NASH has increased even more during the same time period, which is twice that of NAFLD.

NAFLD prevalence in major countries around the world (Document 1) NASH destroys anti-tumor immune surveillance.
Recently, more than 80 research institutions including the German Cancer Center, Novo Nordisk, etc.
, jointly published an article in Nature, explaining that NASH destroys anti-tumor immune surveillance.
It is the destructive molecule of immunotherapy for hepatocellular carcinoma.

Research summary Hepatocellular carcinoma (HCC) has viral or non-viral pathogenic factors, and non-alcoholic steatohepatitis (NASH) is an important driving force of HCC.

Immunotherapy has been approved for the treatment of HCC, but patient stratification based on biomarkers to improve treatment response has not yet made significant progress.

This study found the gradual accumulation of depleted and abnormally activated CD8+PD1+T cells in the liver affected by NASH.

In the preclinical model of NASH-induced HCC, therapeutic immunotherapy with PD1 antibody expanded the activated CD8+PD1+T cells in the tumor, but did not lead to tumor regression, indicating that tumor immune monitoring was impaired.

When preventive treatment, anti-PD1 treatment leads to an increase in the incidence of NASH-HCC and the number and size of tumor nodules, which is related to the increase in liver CD8+PD1+CXCR6+TOX+TNF+T cells.

The increase in HCC induced by anti-PD1 treatment is prevented by CD8 T cell depletion or TNF neutralization, which indicates that CD8 T cells help induce NASH-HCC, rather than activate or perform immune monitoring.

Anti-PD1 increased the number of CD8+PD1+CXCR6+TOX+TNF+T (Reference 2).
Similar phenotypic and functional characteristics were found in liver CD8+PD1+T cells of NAFLD or NASH.

Three randomized phase III clinical trials (CheckMate 459, IMbrave150, KEYNOTE-240) analyzed the PDL1 of more than 1600 patients with advanced HCC and showed that immunotherapy could not improve the survival rate of non-viral HCC patients.

In the other two cohorts, patients with HCC who received anti-PD1 or anti-PDL1 therapy had a decreased overall survival rate compared with patients with other causes.

In summary, these data indicate that non-viral HCC, especially NASH-HCC, may have a weaker response to immunotherapy.
This may be due to NASH-related abnormal T cell activation, leading to tissue damage and impaired immune surveillance.

PD-1 antibody treatment, the overall survival rate of NAFLD-HCC patients is lower than that of the control group (Reference 2) 360 Comments: Non-alcoholic liver disease is a driving factor for hepatocellular carcinoma, and it is also an important factor hindering PD-1 immunotherapy.

Preventing NAFLD is the key to a healthy life.

References Zobair Younossi et al, Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention, Nat Rev Gastroenterol Hepatol.
2018 Jan;15(1):11-20.
Dominik Pfister et al, NASH limits anti-tumour Surveillance in immunotherapy-treated HCC, Nature.
2021 Mar 24.
Note: The copyright belongs to the original author of the article.
Bio360 shares and adds his own opinions.