Abstract
Simple SummaryImmunotherapeutic approaches became a promising treatment option and an intensive field of research in liver cancer. Despite promising results in preclinical studies, only moderate response rates have been reported in phase III clinical trials and predictive biomarkers are still missing. Therefore, translational considerations are important to overcome resistance to immunotherapy. This article reviews potential predictors for response to immunotherapy in hepatocellular carcinoma (HCC) as well as potential mechanisms for therapy resistance. Further, we will discuss translational considerations to overcome therapy resistance in HCC and improve overall response rates.Over the last decade, progress in systemic therapies significantly improved the outcome of primary liver cancer. More recently, precision oncological and immunotherapeutic approaches became the focus of intense scientific and clinical research. Herein, preclinical studies showed promising results with high response rates and improvement of overall survival. However, results of phase III clinical trials revealed that only a subfraction of hepatocellular carcinoma (HCC) patients respond to therapy and display only moderate objective response rates. Further, predictive molecular characteristics are largely missing. In consequence, suitable trial design has emerged as a crucial factor for the success of a novel compound. In addition, increasing knowledge from translational studies indicate the importance of targeting the tumor immune environment to overcome resistance to immunotherapy. Thus, combination of different immunotherapies with other treatment modalities including antibodies, tyrosine kinase inhibitors, or local therapies is highly promising. However, the mechanisms of failure to respond to immunotherapy in liver cancer are still not fully understood and the modulation of the immune system and cellular tumor composition is particularly relevant in this context. Altogether, it is increasingly clear that tailoring of immunotherapy and individualized approaches are required to improve efficacy and patient outcome in liver cancer. This review provides an overview of the current knowledge as well as translational considerations to overcome therapy resistance in immunotherapy of primary liver cancer.
Highlights
Primary liver cancer, in particular hepatocellular carcinoma (HCC) ranks among the most common malignancies worldwide with a rising incidence in the Western world [1,2,3,4]
Until 2016, only limited systemic treatment options were available in advanced stages of HCC, namely sorafenib and regorafenib, tyrosine kinase inhibitors (TKI) [12,13,14]
Several translational studies investigated numbers of immune cells and respective activation of checkpoint molecules as possible biomarkers for immunotherapy response in HCC. In other entities such as non-small cell lung cancer (NSCLC), PD-1high T cells showed a higher capacity for tumor recognition, recruit other immune cells, and are predictive for response and overall survival under PD-1 therapy, which demonstrates that a distinct T cell subtype is needed for response to PD-1/programmed cell death ligand 1 (PD-L1) therapy [79]
Summary
In particular hepatocellular carcinoma (HCC) ranks among the most common malignancies worldwide with a rising incidence in the Western world [1,2,3,4]. Tumor associated macrophages (TAM) represent the predominant component of the innate immune system and promote tumor proliferation, angiogenesis and invasion [34,35] parenchymal cells such as endothelial cells, hepatic stellate cells (HSC), and hepatocytes influence effector functions of infiltrating lymphocytes [21]. Natural killer (NK) cell, important players of innate immunity in the liver, show an impaired function in HCCs [29,37] This dysfunctional and imbalanced immune system is a hallmark of cancer progression in HCC and is associated with patient prognosis. We discuss translational considerations to overcome therapy resistance in HCC
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