The Current Landscape of Immune Checkpoint Blockade in Hepatocellular Carcinoma: A Review

Abstract

Importance: For more than a decade, sorafenib has been the only systemic treatment option for patients with advanced hepatocellular carcinoma (HCC). However, rapid progress over the past few years led to approval of other angiogenesis inhibitors and several immune checkpoint blockers (ICBs) that have been added to the treatment armamentarium for advanced HCC. Moreover, the recent success of a combination of bevacizumab with atezolizumab signals an important change in the front-line treatment of HCC.

Observations: This review summarizes rapidly emerging clinical data on the promise and challenges of implementing ICBs in HCC and discusses the unmet need of biomarkers to predict response or resistance to therapy. Two strategies to target immunosuppression in tumors are also discussed: one proven (vascular endothelial growth factor pathway inhibition) and one currently under investigation (transforming growth factor-β pathway inhibition). The rationale and preliminary evidence on how their inhibition may reprogram the immunosuppressive milieu and enhance the efficacy of ICBs in HCC are reviewed.

Conclusion and relevance: The recent successes and failures of angiogenesis inhibitors and ICBs, alone and in combination, have provided important insights into how to implement this novel systemic therapy in HCC and led to new avenues to enhance immunotherapy efficacy in this disease.

Figure 1.

Effects of Anti-Vascular Endothelial Growth Factor (Anti-VEGF) Treatment on the Tumor Immune Microenvironment A, VEGF-targeted therapy can revert the immunosuppressive effects of VEGF. These effects include the inhibition of dendritic cell (DC) function and maturation, impairment of CD8⁺ T-cell function and infiltration, upregulation of immune checkpoint molecules, as well as the accumulation of immunosuppressive cell types, including tumor-associated macrophages (TAM), myeloid-derived suppressor cells (MDSC), and regulatory T cells (Treg). B, The effects of anti-VEGF treatment are dose-dependent. Higher doses lead to blood vessel pruning and thereby aggravate tumor hypoxia and acidosis, which supports tumor immune evasion. In contrast, low-dose anti-VEGF treatment may normalize the aberrant and dysfunctional tumor vasculature and thereby improve tumor perfusion, alleviate tumor hypoxia, reprogram the immunosuppressive milieu, and increase drug delivery of concomitant therapies, including immune checkpoint blockers (ICBs). Since anti-PD(L)-1 and anti–cytotoxic T lymphocyte antigen-4 antibodies may also normalize blood vessels and make them refractory to pruning by anti-VEGF(R) antibodies, even higher doses of anti-VEGF(R) may normalize tumor vessels when co-administered with immune checkpoint blockers (ICBs).

Figure 2.

The Angiotensin II (AngII)/AngII Type I Receptor Axis Promotes Tumor Immune Evasion by Affecting Cancer Cells as Well as Various Stromal Cells A, AngII activates profibrotic pathways and promotes the deposition of extracellular matrix (ECM) components from fibroblasts. ECM acts as a physical barrier to T-cell infiltration, which hampers an antitumor immune response. ECM also leads to blood vessel compression, which impairs tumor perfusion and aggravates tumor hypoxia and acidosis. The hypoxic and acidic milieu further promotes immunosuppressive mechanisms. B, AngII also induced the secretion of different cytokines and growth factors from cancer and stromal cells. These cytokines inhibit function and accumulation of dendritic cells (DC), natural killer (NK) cells, and T-cells, and promote the accumulation of immunosuppressive cell types, including regulatory T cells (Treg), tumor-associated macrophages (TAM), and neutrophils (TAN), and myeloid derived suppressor cells (MDSC). Finally, tumor hypoxia is further aggravated by AngII-mediated upregulation of vascular endothelial growth factor (VEGF), which increases vascular leakiness and impairs tumor blood perfusion. CAF indicates cancer-associated fibroblast; GM-CSF, granulocyte-macrophage colony-stimulating factor; IL, interleukin; MCP, monocyte chemoattractant protein-1; PGE₂, prostaglandin E₂; and TGF-β, transforming growth factor-β.