Translational Considerations to Improve Response and Overcome Therapy Resistance in Immunotherapy for Hepatocellular Carcinoma

Abstract

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.

Understanding tumour cell heterogeneity and its implication for immunotherapy in liver cancer using single-cell analysis

“…11,118 So far, clinical trials have failed to identify prognostic markers for therapeutic response that are robust enough to stratify patients. 119 Much less is known about mechanisms leading to therapeutic resistance. High PD-L1 expression is associated with response to immunotherapy in NSCLC and melanoma.…”

ELOVLs Predict Distinct Prognosis Value and Immunotherapy Efficacy In Patients With Hepatocellular Carcinoma

“…As an indispensable component of immunotherapy, the TIME has gradually acquired accumulative attention, and the analysis of TIME will contribute to the improvement of immunotherapy responsiveness (42). Some researchers revealed that the TIME could be taken as a main prognostic indicator, which could also enhance the potential of precision treatments (43).…”

Hepatocellular Carcinoma Cells Are Protected From Immunolysis by Mesenchymal Stromal Cells Through Indoleamine 2,3 Dioxygenase

“…Although the results are encouraging, treatment resistance and non-response is a concern ( Dong et al, 2020 ). One of the potential reasons for these discordances could be due to the involvement of other dominant immunoregulatory molecules that play along with PD-L1/PD1 pathway in HCC microenvironment ( Lafleur et al, 2018 ; Heinrich et al, 2020 ; Sharma and Motedayen Aval, 2021 ). Our recent work has identified that PD-L1 is the only molecule in B7 family which exhibits a high correlative expression with tryptophan degrading enzyme, IDO in HCC ( Chinnadurai et al, 2020 ).…”