Elsevier

Surgical Oncology

Volume 26, Issue 4, December 2017, Pages 423-430
Surgical Oncology

Program death-1 immune checkpoint and tumor microenvironment in malignant liver tumors

https://doi.org/10.1016/j.suronc.2017.08.005Get rights and content

Abstract

Hepatic malignancies are one of the leading causes of cancer death globally. Considering the limited efficacy of current standard treatments in management of patients with advanced liver cancers, there has been a growing interest in identifying novel therapies. Despite achieving promising results in initial clinical trials, the therapeutic benefit of immunotherapy is limited due to strong immune-tolerogenic characteristics of liver tumors. Therapeutic regimens that impede tumor immunosuppressive mechanisms or elaborate tumor-specific immunity may improve clinical outcomes of patients with liver malignancies. Programmed cell death 1 (PD-1), an inhibitory checkpoint molecule, and its ligands (PD-L1 and –L2) are the main mediators of immunosuppression within the tumor microenvironment. The expression level of PD-1/PD-L1 may act as a biomarker to predict disease progression, as well as long-term survival. Furthermore, early trials have demonstrated the efficacy and safety of targeting PD-1/PD-L1 as an emerging field in the management of patients with advanced hepatocellular carcinoma. We herein review the role of PD-1/PD-L1 in the pathogenesis of liver malignancies, as well as its potential diagnostic and therapeutic implications.

Introduction

Liver cancer is the sixth most common cancer and third leading cause of cancer death globally. Liver malignancies encompass a wide spectrum of diseases from primary liver cancers such as hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA) to metastatic cancers. Similar to other cancers, liver tumors harbor numerous genetic and epigenetic alterations, which can lead to the production of neoantigens. These neoantigens are recognizable by the immune system and can potentially elicit an endogenous immune response (Fig. 1) [1], [2]. Tumors may, however, evade immune destruction through development of several resistance mechanisms including local immune suppression, induction of immune cell tolerance, and systemic dysfunction in T-cell signaling [3], [4].

Targeting immune checkpoints with small molecules might either turn up (co-stimulatory checkpoint molecules) or turn down (co-inhibitory checkpoint molecules) T-cell signaling. In recent years, inhibitory checkpoint molecules have specifically been investigated as novel targets for cancer immunotherapies (Table 1). One of the most established drugs of this category, Ipilimumab (Yervoy, from Bristol-Myers Squibb), is a monoclonal antibody that inhibits CTLA-4 (an inhibitory checkpoint molecule). In 2011, Ipilimumab gained United Stated Food and Drug Administration (FDA) approval for treatment of patients with advanced melanoma [5], [6]. Programmed cell death 1 (PD-1), another inhibitory checkpoint molecule, and its ligand (PD-L1) have been identified as critical mediators of immunosuppression within the tumor microenvironment (Fig. 2) [7], [8]. Several studies have demonstrated the safety and efficacy of anti –PD-1 and –PD-L1 monoclonal antibodies in the management of patients with advanced cancer [9], [10]. We herein review the role of PD-1/PD-L1 in the pathogenesis of liver malignancies, as well as its potential diagnostic and therapeutic implications.

Section snippets

Mechanisms of immunologic tolerance in the liver

Interferon-gamma (IFN-γ) is an important pro-inflammatory cytokine, which controls production of several downstream effector molecules including CD-40, CD-86, and PD-L1 [11], [12]. PD-L1 expressed by non-parenchymal cells in response to IFN-γ causes immune tolerance by binding to resident T-cells thereby causing apoptosis [13], [14]. Furthermore, the population of immune cells within the liver can recruit myeloid-derived suppressor cells (MDSCs) to the microenvironment. MDSCs following

PD-1/PD-L1 and hepatitis

T-cells antiviral functions are impaired in patients with chronic hepatitis B (HBV) and hepatitis C virus (HCV) infections. In contrast to patients with asymptomatic HBV-infection, the frequencies of HBV-specific CD8+ T cells are similar among patients with active chronic HBV infection (CHBV) and HBV-induced HCC [22]. However, patients with active CHBV and HBV-HCC have significantly reduced HBV-specific CD8+ T-cell response after HBV peptide stimulation. This has been attributed to the

Animal models

In murine liver tissue, PD-L1 is expressed by Kupffer cells (KCs) and liver sinusoidal epithelial cells (LSECs) [28]. PD-L1 deficiency has been demonstrated to lead to hepatic accumulation of T-cells due to impaired apoptosis and enhanced proliferation of effector cells during adenoviral infection [29], [30]. T-cells represent the main mechanism of surveillance against virus-associated tumors, primarily due to the tumors high immunogenicity. The reason that surveillance occasionally fails,

PD-1/PD-L1 and other hepatic malignancies

In addition to HCC, the PD-1/PD-L1 pathway has been implicated in the pathogenesis of other hepatic malignancies including intrahepatic cholangiocarcinoma (iCCA) and colorectal liver metastasis (CRLM) [9], [10], [50]. In a study of 54 patients with iCCA who underwent resection, Gani et al. reported that 34 and 39 specimens were positive for PD-L1 expression on tumor-associated macrophages (TAMs) and cells within the tumor front (TF), respectively [50]. The expression of PD-L1 within the TF was

PD-1/PD-L1 associated biomarkers

In addition to PD-1/PD-L1, other immune-related factors may be useful as biomarkers. For example, neoplastic cells may evade immune surveillance through down regulation of human leukocyte antigens class I (HLA class I). In a study of 80 patients who underwent hepatectomy for HCC, high HLA class I expression was associated with a better recurrence-free survival (RFS), but no difference in OS. Similar to other studies, low expression of PD-L1 was associated with better OS, however the difference

PD-1/PD-L1 inhibition as an adjunct to sorafenib for advanced liver cancer

Considering the limited therapeutic options for patients with advanced HCC, immunotherapy might serve as an adjunct therapy to available treatments. Sorafenib, a multi-kinase inhibitor, is a systemic treatment option for patients with advanced HCC. In addition to its anti-angiogenic effects (via VEGFR inhibition), sorafenib may enhance antitumor immunity [59]. In a murine model of HCC, sorafenib treatment inhibited tumor growth and augmented antitumor immune responses by inducing tumor-specific

Conclusions

PD-1 and its ligands (PD-L1 and L-2) play a critical role in the inhibition of the immune system by inhibiting T-effector cells and inducing immune tolerance. The inhibitory effect of PD-1 is achieved through a dual mechanism of inducing apoptosis in antigen specific T-cells, as well as decreasing apoptosis of Tregs. These effects shape the overall immunity against chronic liver infections and liver malignancies. Restoration of cytotoxic T-cells by blocking the PD-1/PDL-1 pathway may be a

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