Program death-1 immune checkpoint and tumor microenvironment in malignant liver tumors
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
References (64)
- et al.
Oncology meets immunology: the cancer-immunity cycle
Immunity
(2013) - et al.
Mechanisms of immune evasion by tumors
Adv. Immunol.
(2006) - et al.
Regulation of interferon-gamma during innate and adaptive immune responses
Adv. Immunol.
(2007) - et al.
The role of liver stromal cells in dendritic cells development in mice
Transplant. Proc.
(2010) - et al.
PD-1/B7-H1 interaction contribute to the spontaneous acceptance of mouse liver allograft
Am. J. Transplant. Off. J. Am. Soc. Transplant. Am. Soc. Transpl. Surg.
(2010) - et al.
New insights into mechanisms of spontaneous liver transplant tolerance: the role of Foxp3-expressing CD25+CD4+ regulatory T cells
Am. J. Transplant. Off. J. Am. Soc. Transplant. Am. Soc. Transpl. Surg.
(2008) - et al.
B7-H1 determines accumulation and deletion of intrahepatic CD8(+) T lymphocytes
Immunity
(2004) - et al.
Successful chemoimmunotherapy against hepatocellular cancer in a novel murine model
J. Hepatol.
(2017) - et al.
Long-term use of indomethacin leads to poor prognoses through promoting the expression of PD-1 and PD-L2 via TRIF/NF-kappaB pathway and JAK/STAT3 pathway to inhibit TNF-alpha and IFN-gamma in hepatocellular carcinoma
Exp. Cell Res.
(2015) - et al.
Viral infection of tumors overcomes resistance to PD-1-immunotherapy by broadening neoantigenome-directed T-cell responses
Mol. Ther. J. Am. Soc. Gene Ther.
(2015)
The consensus coding sequences of human breast and colorectal cancers
Science
Alterations in signal transduction molecules in T lymphocytes from tumor-bearing mice
Science
Enhancement of antitumor immunity by CTLA-4 blockade
Science
Improved survival with ipilimumab in patients with metastatic melanoma
N. Engl. J. Med.
Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy
Clin. cancer Res. Off. J. Am. Assoc. Cancer Res.
Immune checkpoint inhibition in hepatocellular carcinoma: basics and ongoing clinical trials
Oncology
Safety, activity, and immune correlates of anti-PD-1 antibody in cancer
N. Engl. J. Med.
Safety and activity of anti-PD-L1 antibody in patients with advanced cancer
N. Engl. J. Med.
Tissue expression of PD-L1 mediates peripheral T cell tolerance
J. Exp. Med.
Myeloid-derived suppressor cells as regulators of the immune system
Nat. Rev. Immunol.
Myeloid-derived suppressor cells protect islet transplants by B7-H1 mediated enhancement of T regulatory cells
Transplantation
Hepatic stellate cells regulate immune response by way of induction of myeloid suppressor cells in mice
Hepatology
Immune tolerance in liver disease
Hepatology
The importance of CD25+ CD4+ regulatory T cells in mouse hepatic allograft tolerance
Liver Transplant. Off. Publ. Am. Assoc. Study Liver Dis. Int. Liver Transplant. Soc.
Inhibition of T-cell responses by intratumoral hepatic stellate cells contribute to migration and invasion of hepatocellular carcinoma
Clin. Exp. metastasis
Regulation of HBV-specific CD8(+) T cell-mediated inflammation is diversified in different clinical presentations of HBV infection
J. Microbiol.
The expression of programmed death-1 in circulating CD4+ and CD8+ T cells during hepatitis B virus infection progression and its correlation with clinical baseline characteristics
Gut Liver
Characterization of hepatitis B virus (HBV)-specific T-cell dysfunction in chronic HBV infection
J. Virol.
Upregulation of PD-1 expression on circulating and intrahepatic hepatitis C virus-specific CD8+ T cells associated with reversible immune dysfunction
J. Virol.
Dysfunction and functional restoration of HCV-specific CD8 responses in chronic hepatitis C virus infection
Hepatology
Combined blockade of programmed death-1 and activation of CD137 increase responses of human liver T cells against HBV, but not HCV
Gastroenterology
Expression of programmed death 1 ligands by murine T cells and APC
J. Immunol.
Cited by (18)
Intrahepatic cholangiocarcinoma: Evolving role of neoadjuvant and targeted therapy
2023, Annals of Hepato-Biliary-Pancreatic SurgeryOptimizing Adjuvant Therapy after Surgery for Colorectal Cancer Liver Metastases: A Systematic Review
2023, Journal of Clinical MedicineCurrent status and novel insights into the role of metastasectomy in the era of immunotherapy
2023, Expert Review of Anticancer TherapyPrognostic impact of serum soluble PD-1 and ADV score for living donor liver transplantation in patients with previously untreated hepatocellular carcinoma
2022, Annals of Surgical Treatment and ResearchProtein liposomes-mediated targeted acetylcholinesterase gene delivery for effective liver cancer therapy
2021, Journal of Nanobiotechnology