Molecular underpinnings of immunotherapy in the treatment of hepatocellular carcinoma and surgical implications

Abstract

HCC is a leading cause of cancer related mortality globally and most patients are not diagnosed with this devastating disease until advanced stage. Systemic treatment represents the standard of care for these patients, which, until recently, was only able to provide a modest survival benefit. Recently, the introduction of immunotherapy and more specifically checkpoint inhibitors targeting the PD-1/PD-L1 axis have markedly improved outcomes. As a caveat, however, severe heterogeneity in terms of the survival benefit has been observed. While 15-20% of patients respond to single-agent anti-PD1 treatment and have an outstanding outcome, the majority will exhibit either stable disease or progressive disease where the benefit is severely mitigated. Evidence from other cancer types suggests that tumors with an inflamed microenvironment with heavy effector cell infiltration and an intact antigen-presentation machinery may be more amenable to checkpoint inhibition. The present work incorporates clinical and translational aspects aimed at laying groundwork for the introduction of precision oncology in this space. First, it defines factors driving immunogenicity and immune exclusion in HCC, developing an immune-based molecular tumor classification that characterizes immunogenic and non-immunogenic subclasses through integrative multi-omics analysis. Second, it defines molecular markers predictive of both response and resistance to anti-PD1 using transcriptomic analysis of tumor samples from patients undergoing treatment. Third, through metaanalysis it characterizes the impact of the underlying liver disease on outcomes after immunotherapy for HCC. Increasingly checkpoint inhibitors are tested in earlier disease stages to reduce high recurrence rates after resection. To this end, ensuring a patients availability for adjuvant treatment is contingent on fast recovery after surgery and high quality safety outcomes. The final aspects of this work include a detailed analysis of how laparoscopic liver surgery has facilitated this prerequisite and defines risk factors for adverse outcomes. Together the incorporated reports contribute to our grasp of immunotherapy in the HCC field and provide informative markers that may guide clinical decision making.