NASH limits anti-tumour surveillance in immunotherapy-treated HCC

Area of Science:

• Immunology
• Hepatology
• Oncology

Background:

• Hepatocellular carcinoma (HCC) arises from viral or non-viral causes, with non-alcoholic steatohepatitis (NASH) being a significant driver.
• Immunotherapy shows promise for HCC treatment, yet lacks biomarkers for patient stratification and optimal response prediction.
• Understanding the role of T cells in NASH-associated HCC is crucial for developing effective therapeutic strategies.

Purpose of the Study:

• To investigate the accumulation and activation of CD8+ T cells in NASH-affected livers and their role in HCC development.
• To evaluate the efficacy of programmed death-1 (PD1) targeted immunotherapy in preclinical models of NASH-induced HCC.
• To determine the impact of non-viral etiologies, particularly NASH, on patient response to PD1/PDL1 inhibitors in advanced HCC.

Main Methods:

• Analysis of CD8+ T cell phenotypes (PD1+, CXCR6+, TOX+, TNF+) in NASH-affected livers and HCC models.
• Administration of anti-PD1 immunotherapy in preclinical NASH-HCC models to assess tumor regression and immune cell expansion.
• Meta-analysis of clinical trial data and cohort studies involving patients with advanced HCC treated with PD1/PDL1 inhibitors.

Main Results:

• Progressive accumulation of exhausted, unconventionally activated CD8+PD1+ T cells observed in NASH-affected livers.
• Anti-PD1 therapy in NASH-HCC models expanded CD8+PD1+ T cells but impaired tumor regression, increasing HCC incidence and size.
• Non-viral HCC, especially NASH-HCC, showed reduced survival with anti-PD1/PDL1 treatment, unlike other HCC etiologies.

Conclusions:

• Aberrant CD8+ T cell activation in NASH contributes to HCC development and impairs immune surveillance, rather than enhancing it.
• Non-viral HCC, particularly NASH-HCC, may be less responsive to current immunotherapy due to NASH-related aberrant T cell responses.
• Stratifying HCC patients by etiological factors is essential for optimizing immunotherapy efficacy and improving patient outcomes.