Mechanisms of Resistance to Immunotherapy in Hepatocellular Carcinoma

Abstract

Systemic treatment for advanced hepatocellular carcinoma (HCC) has been revolutionized over the last few years following the approval of immune checkpoint inhibitors (ICI). Despite the promising survival extension seen with ICI combination regimens, responses are not universally seen and the optimal partner for programmed cell death 1 pathway inhibitors remains to be identified. Even fewer encouraging results have been demonstrated with ICI used for monotherapy. Several mechanisms of resistance have been described so far, involving characteristics of cancer cells (intrinsic mechanisms) and of the surrounding tumor microenvironment (extrinsic mechanisms). Factors related to therapy may also contribute to the development of resistance. Increasing research efforts are being dedicated to the discovery of novel approaches and targets to overcome resistance, some of which may be introduced into clinic in the future. Herein we describe a selection of resistance mechanisms that have been involved in impairing response to ICI and propose potential therapeutic approaches to overcome resistance.

Reflections and perspectives on adjuvant treatment in the setting of resected hepatocellular carcinoma

“…Following the promising results of recent randomized clinical trials (RCTs) assessing the survival benefits of combining immune and targeted therapies compared to sorafenib [Table 1] [7][8][9][10][11][12] , researchers have begun evaluating the potential benefits of contemporary systemic therapies in resected HCC. Building on the promising results of the IMbrave150 study, which reported significant survival improvement with atezolizumab plus bevacizumab versus sorafenib in advanced HCC [13] , Qin et al recently reported the interim results of the IMbrave050 study [14] . In this study, the same systemic regimen was administered in an adjuvant setting after resection or ablation of high-risk HCC patients.…”

“…Moreover, in the adjuvant setting of resected HCC, the risk of toxicity must be considered. In the IMbrave050 trial, up to 98% of patients experienced adverse events (AEs), with 41% encountering severe AEs (G3-4), leading to the withdrawal of treatment for 37% of these patients [14] . Notably, these resected patients should be considered cured by surgery, albeit at risk of recurrence.…”