Overcoming Resistance to Immune Checkpoint Blockade in Liver Cancer with Combination Therapy: Stronger Together?

Abstract

Primary liver cancer, represented mainly by hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (CCA), is one of the most common and deadliest tumors worldwide. While surgical resection or liver transplantation are the best option in early disease stages, these tumors often present in advanced stages and systemic treatment is required to improve survival time. The emergence of immune checkpoint inhibitor (ICI) therapy has had a positive impact especially on the treatment of advanced cancers, thereby establishing immunotherapy as part of first-line treatment in HCC and CCA. Nevertheless, low response rates reflect on the usually cold or immunosuppressed tumor microenvironment of primary liver cancer. In this review, we aim to summarize mechanisms of resistance leading to tumor immune escape with a special focus on the composition of tumor microenvironment in both HCC and CCA, also reflecting on recent important developments in ICI combination therapy. Furthermore, we discuss how combination of ICIs with established primary liver cancer treatments (e.g. multikinase inhibitors and chemotherapy) as well as more complex combinations with state-of-the-art therapeutic concepts may reshape the tumor microenvironment, leading to higher response rates and long-lasting antitumor immunity for primary liver cancer patients.

Fig. 1

Reshaping the tumor microenvironment (TME) to reestablish immunosurveillance in primary liver cancer. During the cancer immunity cycle, immunogenic cell death (ICD) and cells of innate immunity recruit professional antigen-presenting cells (APC) to the tumor (1). APC process and present tumor-associated antigens (TAA) during their maturation (2) and relocate to the tumor-draining lymph node (3), where they cross-present and prime naive cytotoxic T lymphocytes (CTL) (4). Following clonal expansion (5), TAA-experienced activated CTL migrate to the tumor and infiltrate the TME (6), where they recognize and kill tumor cells (7). Various mechanisms of tumor immune escape are implemented in the TME, which is represented in four different schematic manifestations (based on Galon and Bruni 50 ). While the hot TME (lower left) shows high CTL infiltration, programmed death ligand 1 (PD-L1) expression and IFN-γ signaling, cold TME (upper left), display near to no CTL infiltration or PD-L1 expression. The excluded TME (upper right) is rich in cancer-associated fibroblasts and T cells in the periphery but not in the tumor center, and the immunosuppressive TME (lower right) shows heightened infiltration of immunosuppressive cells. TME frequencies in HCC and CCA are based on Job et al and Giraud et al. Established and experimental cancer therapies combined with immune checkpoint inhibitor therapy (blue boxes) may alter the TME and facilitate reentry into the cancer-immunity cycle. (Created with biorender.com.) CAF, cancer-associated fibroblasts; CCA, cholangiocarcinoma; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; CXCR, C-X-C-chemokine receptor; DAMP, danger-associated molecular patterns; Flt3L, FMS-like tyrosine kinase 3 ligand; IL, interleukin; FGFR, fibroblast growth factor receptor; HCC, hepatocellular carcinoma; LAG-3, lymphocyte-activation gene 3; MHC, major histocompatibility complex; MKI, multikinase inhibitor; PD-(L)1, programmed death (ligand) 1; TGF-β, tumor growth factor-beta; TIM-3, T cell immunoglobulin and mucin-domain-containing molecule 3; TLR, toll-like receptor; VEGF(R), vascular endothelial growth factor (receptor).

Fig. 2

Intrinsic and extrinsic mechanisms of primary resistance. Tumor intrinsic mechanisms are caused by mutations of genes driving resistance-associated signaling pathways (1) that impair function and efficacy of the immune response by enhancing immunosuppressive properties of regulatory T cells (T _reg ) (2) through stimulated release of immunosuppressive cytokines (3). Reduced availability of tumor-associated antigens (TAA) (4) causes disrupted antigen presentation resulting in impaired activation of cytotoxic T lymphocytes (CTL) (5). Tumor extrinsic mechanisms involve overexpression of programmed cell death ligand 1 (PD-L1) and alternative checkpoints (6) that reduce cytotoxicity of CTL (7), and recruitment of immunosuppressive cells such as cancer-associated fibroblasts (CAF), myeloid-derived suppressor cells (MDSC), tumor-associated macrophages (TAM), and T _reg that prevent tumor infiltration by T cells and NK cells (8). TAM can also promote tumor proliferation (9) and angiogenesis. (Created with biorender.com.) CAF, cancer-associated fibroblasts; CCL, C -C-chemokine; DC, dendritic cell; IFN, interferon; IL, interleukin; MDSC, myeloid-derived suppressor cells; NK, natural killer; PD-(L)1, programmed death (ligand) 1; PTEN, phosphatase and tensin homolog; TAM, tumor-associated macrophage; TGF-β, tumor growth factor-beta; TIM-3, T cell immunoglobulin and mucin domain-containing molecule 3; T _reg , regulatory T cell; VEGF, vascular endothelial growth factor.