Study in ‘Nature’ concludes immunotherapy is less efficient in non-viral liver cancer

From left to right, Josep Maria Llovet, Roser Pinyol, Carla Montironi and Florian Castet, the principal authors of the study.

From left to right, Josep Maria Llovet, Roser Pinyol, Carla Montironi and Florian Castet, the principal authors of the study.

Researchers of the UB and Clínic-IDIBAPS, together with researchers from the German Cancer Research Center in Heidelberg, lead a study that shows patients with hepatocellular carcinoma (HCC) who undergo a type of immunotherapy respond worse to the treatment when the tumor is caused by a fatty liver or alcohol abuse. The study identifies that patients with fatty liver who develop HCC have dysfunctional T lymphocytes, which cannot remove cancer cells nor activate with immunotherapy. This discovery will have important implications in the management of patients with HCC and fatty liver.

The study, published today in the journal Nature, was coordinated by Josep M. Llovet, professor at the Faculty of Medicine and Health Sciences of the UB, ICREA professor at IDIBAPS, where he leads the research group Translational Research in Hepatic Oncology, and director of the Liver Cancer Program at Icahn School of Medicine at Mount Sinai (New York). Other participants in the study were Roser Pinyol, Carla Montironi and Florian Castet, members of the IDIBAPS group.

Causes of hepatocellular carcinoma

Liver cancer is the sixth most common tumor worldwide and the fourth most common cause of cancer death. It is estimated that by 2025, its incidence will exceed 1 million new cases worldwide. Hepatocellular carcinoma is the most common type of liver cancer and can have viral origins (infection due to hepatitis B or C virus), or non-viral (alcohol abuse or as a result of a fatty liver due obesity or diabetes, known as non-alcoholic steatohepatitis). The fatty liver features a current prevalence of 25% in the world and it already causes about 20% of HCC cases in Europe and the United States.

Regarding treatment, for early and mid HCC, there are surgical treatments (resection and liver transplantation) or loco-regional (radiofrequency and chemoembolization). However, nearly half the patients with this cancer will receive pharmacological treatments, either with molecular therapy or with immunotherapy. Immunotherapy can bring clinical benefits in advanced phases of the disease, “as stated in a study published in 2020 on the improvements of survival in patients with advanced HCC who were treated with a combination of two monoclonal antibodies (bevacizumab and atezolizumab)”, notes Josep M. Llovet.

However, the efficiency of immunotherapy can be affected by the cause of the tumour (be it viral, alcohol or fatty liver), since the etiology will condition the type of immune response. “We need biomarkers that correlate with the response to treatment and that enable us to classify patients who can benefit from it”, states Llovet.

Regarding the growing incidence of non-alcoholic steatohepatitis among population, which affects more than 200 million people worldwide, and the risk of developing HCC, researchers assessed the effects of immunotherapy in this context, specifically in PD-1/PD-L1 inhibitors, and how it affects to the tumour progression in animal models and in patients.

Lack of response to immunotherapy in animal models

The first thing researchers observed is that, in animal models with non-alcoholic steatohepatitis, there is an accumulation of T cells of a special type (CD8+PD1+) that are dysfunctional. These types of cells are unable to remove cancer cells and do not activate the anti-tumoral response with the immunotherapy treatment.

Therefore, immunotherapy with PD-1/PD-L1 inhibitors aimed to restore the function of these cells, in the context of fatty liver, does not lead to tumour regression but it has no impact and it causes the accumulation of these dysfunctional lymphocytes. “On the other hand, we saw that the elimination of these dysfunctional lymphocytes in animal models stops tumour formation”, highlights Josep M. Llovet.

The importance of knowing the cause of the tumour in immunotherapy

After researchers assessed the effects on animal models, they analysed three phase III clinical trials with more than 1,650 patients on whom immunotherapy had been assessed (nivolumab, pembrolizumab, or atezolizumab with bevacizumab) in advanced liver cancer and they studied the response according to the liver disease that caused the tumour. The analysis shows that these immunotherapies are efficient in viral-cause HCC (hepatitis B and C viruses), but they do not increase the survival of patients with non-viral HCC.

This discovery has clinical implications –in the management of patients with HCC with these aetiologies– as well as implications from a research perspective.

“In the short run, we will need to consider the use of immunotherapy in patients with non-viral HCC more carefully and consider approved therapeutical alternatives (kinase tyrosine inhibitors). Also, we will need clinical trials that assess new therapeutical combinations for patients with non-viral HCC. Actually, the experimental knowledge obtained in this study provides the bases for the design of combination treatments to overcome current limitations and improve the survival of these patients”, notes Josep M. Llovet.

Study reference:

Dominik Pfiste, Nicolás Gonzalo Núñez, Roser Pinyol, et al. «NASH limits anti-tumour surveillance in immunotherapy-treated HCC». Nature, March 2021. DOI:

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