Immunotherapy for nonalcoholic fatty liver disease-related hepatocellular carcinoma: Lights and shadows

Abstract

About one-fourth of adults globally suffer from nonalcoholic fatty liver disease (NAFLD), which is becoming a leading cause of chronic liver disease worldwide. Its prevalence has rapidly increased in recent years, and is projected to increase even more. NAFLD is a leading cause of hepatocellular carcinoma (HCC), the sixth-most prevalent cancer worldwide and the fourth most common cause of cancer-related death. Although the molecular basis of HCC onset in NAFLD is not completely known, inflammation is a key player. The tumor microenvironment (TME) is heterogeneous in patients with HCC, and is characterized by complex interactions between immune system cells, tumor cells and other stromal and resident liver cells. The etiology of liver disease plays a role in controlling the TME and modulating the immune response. Markers of immune suppression in the TME are associated with a poor prognosis in several solid tumors. Immunotherapy with immune checkpoint inhibitors (ICIs) has become the main option for treating cancers, including HCC. However, meta-analyses have shown that patients with NAFLD-related HCC are less likely to benefit from therapy based on ICIs alone. Conversely, the addition of an angiogenesis inhibitor showed better results regarding the objective response rate and progression-free survival. Adjunctive diagnostic and therapeutic strategies, such as the application of novel biomarkers and the modulation of gut microbiota, should be considered in the future to guide personalized medicine and improve the response to ICIs in patients with NAFLD-related HCC.

Obesity contributes to hepatocellular carcinoma development via immunosuppressive microenvironment remodeling

“…Anti-PD-L1 & anti-angiogenic immunotherapy (atezolizumab in combination with bevacizumab) is currently the first-line treatment for advanced HCC. A subgroup analysis of survival outcomes based on the trials evaluating the efficacy of ICIs as first-line therapy showed that viral-HCC could benefit from ICIs ( 168 ). However, for non-viral-HCC patients, ICIs were not observed to be superior to sorafenib, which suggested that obesity may be not a positive marker for ICI therapy in HCC.…”

Nonalcoholic Fatty Liver Disease-Related Hepatocellular Carcinoma: The Next Threat after Viral Hepatitis

“…Analyses of survival outcomes in subgroups evaluating the efficacy of ICIs as first-line treatment revealed a discrepancy between viral HCC and non-viral HCC, including NASH-related HCC. Tremelimumab plus Durvalumab was the only combination of two ICIs tested against sorafenib in the first-line setting, and the only one that showed a relatively higher OS in the non-viral and viral HCC subgroups [ 61 , 62 ].…”

“…Other studies showed that patients with NASH-driven HCC treated with anti-PD1 or anti-PDL1 showed poorer survival than patients with HCC due to other etiologies. Overall, these data show that NASH-HCC is less responsive to immunotherapy due to NASH-related abnormal T cell activation that induces tissue damage and leads to impaired immune surveillance [ 62 ].…”

“…The prevention strategy starts by adopting a change in multiple lifestyle factors, which can lead to a significant reduction in HCC incidence in general populations. This highlights the importance of promoting healthy living for the primary prevention of HCC [ 62 ]. Lifestyle interventions and chemoprevention are the main possible methods of HCC prevention in patients with NAFLD [ 63 ].…”