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Immune Control in Hepatocellular Carcinoma Development and Progression: Role of Stromal Cells Peter R. Galle, MD, PhD1

1 First Medical Department, University Medical Center,

Johannes Gutenberg University, Mainz, Germany Semin Liver Dis 2014;34:376–388.

Abstract

Keywords

► hepatocellular carcinoma ► macrophages ► myeloid suppressor cells ► tumor environment ► immune surveillance

Address for correspondence Peter R. Galle, MD, PhD, First Medical Department, University Medical Center, Johannes Gutenberg University, Langenbeckstrasse 1, 55131 Mainz, Germany (e-mail: [email protected]).

Immune control of hepatocellular carcinoma (HCC) is executed by effector immune cells, which efficiently eliminate malignant transformed cells. However, progression of HCC clearly documents failure of tumor immune control, which led to the concept of immune subversion by the tumor environment. Particularly tumor-associated stromal cells cooperate within an inflammatory network, which is responsible for immune privilege. The stromal cell composition matures during tumor growth and is derived from surrounding noncancerous tissue or from circulating cells recruited to the tumor site. Therefore, immunosuppressive stromal cells represent heterogeneous cell lineages, including myeloid cells, lymphocytes, endothelial cells, and fibroblasts, which interact by direct cell contact, secretion of soluble factors, or production of extracellular matrix. As the stromal cells determine tumor immune control and clinical outcome of HCC, they represent a promising target for cancer immunotherapy.

Epidemiological data clearly support inflammation driven development of hepatocellular carcinoma (HCC), as chronic viral hepatitis B and C as well as nutritive-toxic hepatitis are the most prominent causes of HCC. 1 In these heterogeneous entities, sequence of liver fibrosis, cirrhosis and HCC is clearly related to the inflammatory activity in the liver, 2–4 which involves cell types from the innate and adaptive immune system. Several experimental tumor models confirm that chronic inflammation initiates early hepatocarcinogenesis and eventually drives tumor progression. 5–11 Throughout this process, HCC is exposed to an ambivalent inflammatory environment, as chronic unresolved inflammation promotes cancer development, whereas profound immune control is able to prevent tumor progression. In this context, protective immune surveillance is generally executed by tumor-directed natural killer (NK) cells and lymphocytes, which efficiently recognize and delete malignant cells. However, tumor growth clearly documents failure of tumor

Issue Theme Hepatocellular Carcinoma: Current Evidence and Future Research; Guest Editor, Jordi Bruix, MD

immune control suggesting inhibition of anticancer immune responses. Stromal cells associated with HCC mirror the complex inflammatory network responsible for the immune-privileged tumor milieu. The stromal cell composition evolves during an inflammatory adaption, which starts with tumor induction and matures during tumor growth. This process requires selective recruitment, differentiation, and activation of immune modulatory cells. Stromal cells hereby interact with the malignant tissue by direct cell contact, secretion of soluble factors, or production of extracellular matrix. This takes into account that stromal components may also be located outside the primary HCC in adjacent noncancerous liver tissue. Following these considerations we will outline the prime mechanisms of anticancer immune control and highlight the HCC-associated stromal cell components affecting tumor immune surveillance. Particularly, as HCC-associated immune-modulatory cells are potential targets of anticancer immune therapy.

Copyright © 2014 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.

DOI http://dx.doi.org/ 10.1055/s-0034-1394138. ISSN 0272-8087.

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Martin F. Sprinzl, MD1

Immune Control during HCC Initiation and Progression Innate Immune Control of HCC Innate immune responses are capable to eliminate malignant cells and belong to the first-line defense to control tumor initiation and progression. Particularly, NK cells (CD3-/ CD56þ) reside in the liver and represent approximately 30% to 50% of the hepatic lymphocytes in humans.12–14 Natural killer cells, therefore, represent a relevant effector cell population contributing to tumor surveillance within the liver. Tumor control by NK-dependent elimination of senescent tumor cells was conclusively shown in a murine hepatoma model.15 Natural killer cells also control tumor progression of transplanted tumors of different etiology in mice.16 The balanced activation of NK cells is tightly regulated by activating and inhibiting receptors,17 which facilitate selective tumor cell elimination by granzyme-B, TRAIL and FAS-ligand(FasL-) dependent cytotoxicity.18–21 The NK cell receptor NKG2D and its corresponding ligands in mice (H60 and Rae1) and humans (MICA/B) are well-characterized activators of anticancer NK cell response.16,22 In this context, NKG2D ligands are predominantly expressed by transformed cells, which selectively promote tumor-directed NK cell cytotoxicity.16,23,24 However, regulation of NK cell activation also includes inhibitory NK receptors, which bind to major histocompatibility complex (MHC) class I molecules and belong to the inhibitory killer Ig-like receptor (KIR) family.17 Downregulation of MHC-class I surface expression on malignant cells restrains NK cell inhibition and promotes tumor-directed responses. A part of direct cell-interaction NK cells is incorporated in a cytokine network of IL2, IL12, IL15, and type I interferons, which increase their viability, proliferation, and cytotoxicity.25,26 In return, activated NK cells release granulocyte-macrophage colony-stimulating factor (GMCSF) and interferon-γ (IFN-γ),27,28 which eventually support maturation of antigen-presenting cells and drive Th1 responses to control the tumor. Eventually, NK cells expressing Fc receptor (CD16) also execute anticancer B cell responses as they facilitate antibody-dependent cellular cytotoxicity of opsonized tumor cells.29 The relevant contribution of NK cells to HCC control in humans is indicated by prolonged recurrence-free survival after resection of HCC in presence of increased cytotoxic NK cell activity or tumor NKG2D-ligand (UL16-binding protein 1) expression.30,31 Corresponding histological analysis also correlated proliferating NK cells (CD56þ/Ki67þ) in HCC with tumor cell apoptosis, which linked NK cell activation and target cell killing.32 High TRAIL-receptor (DR4, DR5) expression and low MHC-I expression in HCC further emphasizes the sensitivity of HCC against NK cell responses.33,34 Indirect evidence for NK-cell-driven HCC control is provided by the prognostic value of peritumoral IL2 and IL15 expression, which represent potent NK cell activators.33,35 Natural killer T (NKT) cells, another component of innate tumor defense, represent approximately 5% to 10% of the entire hepatic NK cell population. NKT cells close a link between innate and adaptive immunity as they express NK

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cell markers beside invariant T cell receptors to detect pathogen-associated molecular patterns.12 Natural killer T cells provide cytotoxic effector functions and important regulatory functions during immune response priming. Their contribution in antitumor immune control has emerged in recent years as NKT cells are capable to eliminate tumors upon specific stimulation with α-galactosylceramide, which is recognized by the T-cell receptor (TCR) repertoire expressed on NKT cells.36,37 In addition, CD1 knockout mice as well as IL12 receptor deficient mice, lacking efficient NKT cell responses, show impaired tumor control.38,39 The activated NKT cells either execute direct lytic activity or prime secondary-tumor-directed immune responses via secretion of IFN-γ.40–42 In patients with chronic hepatitis C, the responsiveness of hepatic NK and NKT cells is reduced during cirrhosis progression, resulting in low-lytic activity and IFN-γ release upon tumor cell contact.43 The progressive NK/NKT dysfunction is associated with an increased HCC risk and suggests hampered innate tumor surveillance in cirrhosis.43 Accumulation of NKT cells in HCC tissue provides further evidence for innate tumor-directed immune responses, particularly if NKT cell infiltrations were combined with elevated IFN-γ expression.44 However, HCC progression along with increasing NKT tumor infiltration indicate impaired anticancer effects in the tumor environment45 some findings even suggest NKT-driven tumor immune escape.46

Adaptive Immune Control of Hepatocellular Carcinoma Adaptive tumor surveillance develops along with innate immune responses, which eventually target tumor-associated antigens (TAA). Therefore, specific elimination of transformed cells by adaptive immune responses protects from tumor manifestation and progression. Adaptive immunity involves CD4þ T lymphocytes, which represent different helper lineages (including Th1, Th2, Th17), defined by specific cytokine secretion profiles. The fundamental role of CD4 T cells in early tumor prevention via senescent cell elimination has been confirmed in a murine HCC model.47 The mechanism of CD4 T cell dependent tumor surveillance is based on Th1-polarized responses, which eventually drive macrophages to deplete senescent cells. The cytokine milieu associated with T-cell polarization guides immune responses responsible for tumor control. Particularly, local Th1-polarized T cell responses in human HCC support favorable prognosis.48 Thus, Th1-cytokines (IL1A, IL1B, IL2, and IFN-γ) are prominently expressed in localized HCC, whereas Th2-cytokines (IL4, IL5, IL8, and IL10) are present in HCC with vascular invasion and metastasis.48 Furthermore, expression of T-cell-promoting cytokines (IL2 and IL15) in peritumoral tissue is associated with a low HCC recurrence rate following resection.35 Despite these facts, TAA-specific CD4 T lymphocytes were not observed in HCC patients under normal circumstances so far, indicating impaired T-cell help in established HCC.49,50 However, detection of tumor-specific antibodies in HCC patients provides indirect evidence for Th2-skewed help, which orchestrates Bcell response and antibody production.51 As circulating antibodies recognize different HCC-associated antigens, they may Seminars in Liver Disease

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Immune Control in Hepatocellular Carcinoma Development and Progression: Role of Stromal Cells

Immune Control in Hepatocellular Carcinoma Development and Progression: Role of Stromal Cells be relevant for HCC immune surveillance.51–53 Yet no clear correlation between tumor-reactive antibodies and clinical outcome has been established. Th17-polarized immune cells represent another distinct Tcell lineage, which differs from Th1/Th2-lymphocytes by secretion of IL17.54 Th17 lymphocytes are promoters of autoimmune disease and typically contribute to pathogen defense.55 Th17 cell involvement in tumor control has been confirmed in murine tumor models56–58 and Th17 cells are associated with different human cancer entities.59–61 Albeit Th17 lymphocytes show diminished cytotoxic effector function, they are capable to prime cytotoxic T cells involved in tumor control.56,58,62 In HCC patients, activation of Th17polarized responses following chemoembolization is associated with improved outcome and supports their contribution to tumor surveillance.63 However, conflicting data correlate Th17 lymphocyte infiltrations in HCC with poor prognosis,61 which may reflect the activation of Th17 responses by tumorpromoting cytokines.5,64–66 Cytotoxic CD8 T cells (CTL) are the basis of immunological tumor surveillance, as they efficiently eliminate transformed cells. CTL effector functions are unleashed, following the TCR binding to the corresponding MHC/antigen complex expressed on tumor cells. Eventually CTL killing is mediated by FasL, perforin, and granzyme B expressed or secreted during activation.67 First data showing therapeutic tumor control by CTL in humans was provided by TAA-specific responses, which maintained remission of chronic myeloid leukemia following bone marrow transplantation.68 Evidence for their impact on solid tumor progression has eventually stretched out on HCC, which is regarded as potential target for cytotoxic T-cell-based interventions.69 CTL infiltrations in HCC tissue are a prognostic factor for prolonged diseasefree survival and overall survival after HCC resection.70 Corresponding tumor-directed cytotoxic CD8 T cell responses

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are present in patients with established HCC (►Table 1). These T cells recognize TAA expressed in the HCC tissue, such as α-fetoprotein, glypicane-3, NY-ESO-1, and MAGE.51,71–75 Their prognostic relevance has been confirmed in patients receiving local ablative therapy, where tumordirected T cells indicate better tumor response.76,77 However, effective T-cell responses are limited by low T-cell frequencies and impaired T-cell function. The lack of function is largely attributed to central tolerance caused by thymic deletion of autoreactive T cells, leading to a low TCR affinity against TAA compared with the naïve T-cell repertoire.78 Expression of the checkpoint molecule programmed cell death protein-1 (PD-1) by HCC-infiltrating lymphocytes indicates additional T-cell exhaustion with functional impairment.75 The mechanism of T-cell exhaustion has been conclusively confirmed in a murine model of SV40 large T-antigen (TAg-) inducible HCC.79 In this model, the initial elimination of nearly all TAgþ hepatocytes was followed by development of TAgþ tumors along with hepatic accumulation of TAg-specific PD-1þ CD8 T cells. Local tolerance was concluded, as TAgþ cancer cells expressing a luciferase reporter were rejected at a subcutaneous injection site, whereas the same cancer cells established tumors in the permissive HCC environment.79

HCC Associated Stromal Cells and Immune Control HCC-Associated Stromal Cells from the Local Environment Hepatocellular carcinoma progression in the presence of innate and adaptive immune effector mechanisms documents inhibition of tumor immune surveillance. Stromal cells associated with HCC have entered research focus in recent years, as they are key inducers of local immune tolerance. The

Table 1 Hepatocellular carcinoma directed cytotoxic T-cell responses T cell target antigen

Source

Method

MAGE-A1

PBMC, HCC

ELISPOT, Tetramer

MAGE-A2

HCC

ELISPOT

MAGE-C2

HCC

ELISPOT

SSX-2

HCC

ELISPOT, ICS

Outcomea

Reference

Local ablation

Increased RFS, PFS

72,75,76,180

NR

NR

75

NR

NR

75

NR

NR

75

Clinical setting

GPC-3

PBMC, HCC

ELISPOT

Local ablation

Increased RFS, PFS

72,76

NY-ESO-1

PBMC, HCC

ELISPOT, ICS, CSA

Local ablation

Increased PFS

51,75,76

hTERT

PBMC, HCC

ELISPOT, ICS; CrR

Local ablation

Increased PFS

71,75,77

AFP

PBMC, HCC

ELISPOT, ICS; CrR

Local ablation / NR

Increased PFS

72,74,77

p53

PBMC

ELISPOT, ICS; CrR

NR

NR

71

SART-3

PBMC

ELISPOT, ICS; CrR

Local ablation

Increased PFS

71,77

MRP-3

PBMC

ELISPOT

Local ablation

Increased PFS

71,77

Abbreviations: AFP, α-fetoprotein; CSA, cytokine secretions assay; CrR, chromium release assay; ELISPOT, enzyme-linked immunospot; GPC-3, glypicane-3; hTERT, human reverse transcriptase telomerase; ICS, intracellular stain; MAGE, melanoma-associated genes; MRP-3, multidrug resistanceassociated protein-3; NR, not rated; RFS, recurrence-free survival; SART-3, squamous cell carcinoma antigen recognized by T cells 3; SSX-2, synovial sarcoma X chromosome breakpoint. a Clinical data related to outcome are provided in references 72,76,77. Seminars in Liver Disease

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Immune Control in Hepatocellular Carcinoma Development and Progression: Role of Stromal Cells

Liver Sinusoidal Endothelial Cells Liver sinusoidal endothelial cells (LSECs) line the sinusoidal space and are directly exposed to the portal blood flow, which contains nutrient-derived antigens and lipopolysaccharides (LPSs) from intestinal bacteria. Therefore, LSECs shield the liver from incoming antigens and are the prime checkpoint to shape local immune tolerance. Liver sinusoidal endothelial cells efficiently clear LPS from the portal system, which leads to a reduced MHC-dependent antigen presentation on LSEC. LPS exposure further prevents lysosomal antigen processing and downmodulates costimulatory CD80 and CD86 expression in LSECs.80 Induction of programmed death ligand-1 (PD-L1, B7-H1) on LSEC also promotes coinhibitory PD-1 signaling, which induces CD8 T cell tolerance.81 PD-L1 hereby binds to PD-1, which is an immunoglobulin superfamily member related to CD28 and CTLA-4, incapable to transduce activating signals to T cells. LSEC lack IL12 expression and secrete Th2-polarizing factors upon stimulation, which prime Th0 (IL4, IL10, IFN-γ) T cells, but fail induction of Th1 responses.82 Interestingly, the robust Th0-polarized T-cell phenotype is not affected by stimulatory cytokines (IL1, IL12, and IL18) and is only inhibited by neutralizing anti-IL4 antibodies during LSEC priming.80 Activation of LSECs also induces regulatory CD4 T-cell (Treg) populations of CD25low FoxP3- phenotype and induce classical CD25high FoxP3þ Tregs in a TGF-β dependent

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manner.83,84 The role of LSECs in early HCC progression is supported by histological findings, which confirm endothelial cells (positive for Stabilin-1/2, LYVE-1, and CD32b) in close vicinity to malignant cells and in the peritumoral tissue.85 Throughout tumor progression, the LSECs are displaced by the expanding tumor supporting their hepatic origin. Nevertheless, presence of LSEC markers in the HCC environment is associated with impaired outcome.85,86

Hepatic Tissue Macrophages (Kupffer Cells) Kupffer cells (KCs) are the most prominent hepatic tissue macrophages, which could contribute to local tolerance. KCs are found close to the sinusoids and have access to the portal blood circulation. They share functional features of alternatively polarized macrophages, as they produce TGF-β and IL10 upon LPS stimulation via Toll–like receptor (TLR-) 4.84,87,88 Kupffer cells derived TGF-β induces CD25high FoxP3þ Tregs,84,89 whereas IL10 suppresses NK-cell function90 and Th1 responses.87,91 Corresponding mouse data indicate that KCs are essential to establish Treg-driven hepatic tolerance against antigen challenge in vivo.92 KCs also produce prostaglandin E2 (PGE-2) upon stimulation,93,94 which regulates activation of myeloid-derived suppressor cells (MDSC).95 Recruitment of regulatory cell types link KCs function to cancer immune evasion, as Treg and MDSC are associated with HCC progression.96,97 Inhibitory PD-L1 expressed on KCs directly transduces tolerizing signals to cytotoxic T cells via PD-1. This mechanism eventually drives T-cell inhibition in context of the tumor milieu, as IL10 secreted by hepatoma cells increases PD-L1 expression on KCs.98 Tolerogenic capacity of KC has also been attributed to their surface expression of galectin-9, which is upregulated by IFN-γ during inflammation in HBV-associated HCC.99 Galectin-9 induces cell death in TIM-3 expressing lymphocytes and tempers Th1 responses.100 Coherent data show that galectin-9 expressed by KCs induces senescence of TIM-3þ T cells in HCC, which accumulate in HCC and determine outcome.99 The finding is

Fig. 1 Stromal cell architecture in hepatocellular carcinoma (HCC). (A) Early HCC lesions develop in the immune-privileged niche of hepatic trabeculae. Liver sinusoidal endothelial cells (LSECs) separate hepatocytes and tumor cells from the sinusoidal lumen, which drains the hepatic blood from the portal system to the central vein. LSECs and Kupffer cells sense circulating immune stimulators (e.g., nutrient antigens, LPS), secret anti-inflammatory cytokines (IL10, TGF-β) and prevent efficient T-cell priming. Chronic inflammation activates hepatic stellate cells, which shape the inhibitory environment by production of cytokines and extracellular matrix. (B) Established HCC replaces the hepatic micro-architecture by pauci-immune tumor tissue. Hepatic tissue collapse during HCC expansion and myo-/fibroblast activation results in a peritumoral accumulation of extracellular matrix. HCC typically accumulates stromal cells at the invasion front or at the margin of necrotic areas. The stromal cells are either derived from the neighboring noncancerous tissue or from the circulating pool of immune cells.

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stromal cells associated with HCC are initially derived from the hepatic tissue, which provides an immune-privileged niche for early tumor lesions and shapes the surrounding noncancerous tumor environment (►Fig. 1). Hepatic tolerance, which copes with continuous immune stimulation by immunogenic components absorbed in the gastrointestinal system, provides an ideal foundation for tumor progression. Liver cirrhosis, which forms the background of most HCC, further accentuates the immune-modulatory functions of the hepatic environment.

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Immune Control in Hepatocellular Carcinoma Development and Progression: Role of Stromal Cells in line with the controversial hepatic “graveyard theory,” which suggests tolerance induction by deletion of activated T cells in the liver.101 However, the effect of KCs on tumor progression remains unresolved, particularly as depletion of KCs in a model of hepatic metastasis promotes cancer growth.102 These contrasting results may reflect the functional plasticity of KC depending on the underlying inflammatory stimulus. Thus, toll-like receptor (TLR-) 3 engagement by Poly I:C on KCs induces secretion of IL12 and IL18, which may promote effector cell responses with antitumor activity.90

Cirrhotic Liver Environment Hepatocellular carcinoma develops during chronic liver damage accompanied with destructive liver fibrosis. The typical noncancerous tissue harboring the HCC therefore shows a cirrhotic liver architecture in approximately 80% of all cases.103 Cirrhotic liver anatomy increases portal pressure, which promotes translocation of intestinal bacteria into the portal circulation. Consecutive increase of LPS activates LSECs and KCs, which drive hepatic immune privilege. LPS, reactive oxygen species (ROS) from activated KCs, or stromal-derived factor 1α (SDF-1α) secreted by LSECs further induce hepatic stellate cells (HSCs), which enhance tumor progression, produce collagen and are the main storage of retinoic acid.104–107 Again, activated HSCs induce regulatory T cells via secreted Th2-type cytokines or retinoic acid,108,109 which has a major impact on immune control of HCCs.110 HSCs have also been identified as inducers of MDSC, which may inhibit alloreactive T-cell responses111,112 and hamper tumor response during systemic HCC therapy.113 Additional crosstalk between activated HSCs and T cells engages PD-1/PD-L1 interaction leading to T-cell exhaustion.114,115 Evidence also supports that HCSs transdifferentiate to myofibroblasts or fibroblasts and shape the HCC environment. This particularly accounts for the characteristic peritumoral fibrotic capsule, which evolves from myofibroblasts expressing smooth muscle actin-α (SMA-α).116 Initial data attributed accelerated hepatoma cell growth and HCC progression to the growth factor release by activated HSCs or fibroblasts.117,118 However, similar SMA-α positive fibroblasts promote tumor invasion of desmoplastic carcinomas via SDF-1/CXCL12 secretion119 and recruit macrophages to the tumor site.120 Therapeutic fibroblast elimination even reduces macrophage (F4/80) tumor infiltrations in a murine mamma carcinoma model and restored intratumoral cytotoxic (granzyme-Bþ) CD8 T cell frequencies.121 These data indicate either direct T-cell inhibitory effects of fibroblasts or indirect immune modulation by recruited macrophages. Direct NK-cell inhibition was recently confirmed in coculture experiments with HCC-associated fibroblasts. Specific inhibitors of fibroblast signaling restored NK-cell cytotoxicity after target cell contact and identified PGE-2 and indoleamine 2,3dioxygenase (IDO) as inhibitory factors secreted by fibroblasts.122 However, the complete impact of the cirrhotic HCC environment on immune surveillance has just started to reveal. Seminars in Liver Disease

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This includes the role of platelet stimulation during portal hypertension. This hypothesis is supported by elevated sCD40L serum concentrations in cirrhotic patients, as sCD40L is released from activated platelets into the circulation of cirrhotic patients.123 Analysis of TAg-induced HCC shows early thrombocyte aggregation and sequential macrophage recruitment within the dysplastic stroma, supporting the role of thrombocytes in HCC formation.124 Along with platelet activation tumor cells may be shielded against cytotoxic NK cells, which might affect innate tumor control.125 Activated thrombocytes also release vascular endothelial growth factor (VEGF), which could induce regulatory T cells.126 However, more research is required to unravel the interaction between HCC stroma, coagulation, and immune control in liver cirrhosis.

HCC-Associated Stromal Cells from the Circulation Throughout HCC progression, selective recruitment of circulating immune modulatory cells determines the stromal cell composition (►Fig. 1). The privileged milieu is eventually maintained by tumor-derived factors, which differentiate and activate immunosuppressive stromal cells. Hence, tumorassociated stroma cells do not delineate entirely from the local tissue context and are regularly recruited to the tumor site from the blood circulation (►Fig. 2). Circulating stromal cell precursors are typically derived from myeloid or lymphocytic cell lineages. The coordinated expression of chemokines on endothelial cells and malignant cells finally navigates the immune cells to the tumor stroma.127 Local chemokines determine the composition of effector or regulatory immune cells, which express cell specific chemokine receptors families (CCR, CXCR, CX3CR, and XCR).128 Lymphocyte recruitment to HCC tissue is mediated by CXCR3 or CCR5 and their corresponding chemokine ligands. This is confirmed by monoclonal antiCXCR3 and anti-CCR5 antibodies inhibiting tumor lymphocyte infiltration in tumor bearing mice.127 The increased CXCR3 expression in HCC-infiltrating lymphocytes compared with their circulating counterparts supports CXCR3selective lymphocyte recruitment to the tumor.129 Corresponding data correlate CXCL10, CCL5, and CCL2 expression in resected HCC with protective Th1-skewed lymphocyte infiltration associated with improved outcome.130 However, downregulation of CXCR3 in HCC patients compared with healthy controls could also indicate disrupted T-cell recruitment into cancer.131 In turn, CCL22-dependent mechanisms recruit regulatory CD4 T cells (Treg) to the tumor environment, which express CCR4 and represent the immunosuppressive counterpart of effector lymphocytes.132 CCL22dependent Treg-recruitment signaling has been confirmed in HCC and is driven by chronic inflammation and TGF-β release during chronic hepatitis B.133 The CXCL12-CXCR4 axis is also relevant for stromal cell composition as it recruits myeloid-derived cell subsets to the tumor environment.113 CXCR4 has regularly been confirmed in HCC tissue and its high expression may result from impaired TGF-β inhibition or from the rigid HCC matrix.134–136 Endothelial cells and HSCs associated with HCC

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Fig. 2 Crosstalk between effector immune responses and stromal cells in the tumor. (1) Chemokines originating from the tumor environment recruit stromal cells and effector immune cells. (2) Effector immune cells specifically recognize and eliminate malignant tissue. (3) Factors derived from the tumor polarize anti-inflammatory (M2) tumor-associated macrophages, which stimulate inhibitory regulatory T cells (Treg), myeloidderived suppressor cells (MDSC), and myofibroblasts. (4) M2 macrophages directly inhibit cytotoxic T cells and induce Th2-skewed responses, which in turn stimulate M2-macrophages via IL4. (5,6) Stimulated Tregs and MDSC eventually inhibit tumor specific T cell and NK/NKT cell responses, (7) whereas stimulated fibroblasts shape the immune milieu by production of extracellular matrix and soluble cytokines.

are potential sources of CXCL12 (SDF-1α) to drive CXCR4dependent myeloid cell attraction. Conditional myeloid (MxCre) CXCR4-ko mice show reduced myeloid (Gr1þ) cell recruitment into lung cancer, which results in impaired tumor growth in combination with disrupted VEGF signaling.137 Inhibition of CXCR4 signaling with AMD3100 reduces myeloid (Gr1þ) cell frequencies in HCC as well.113 Chemokines may also drive recruitment of macrophages to HCC, given that myeloid precursors may differentiate into macrophages.138 However, the recruitment of macrophages to the HCC environment remains controversial, as resident KCs are mainly involved in HCC induction.10 Presumably local (KCs) and distant macrophage populations contribute to the accumulation of tumor-associated macrophages (TAMs) in HCC.

Dendritic Cells Activated macrophages recruit dendritic cells (DCs) from the sinusoidal circulation, which home in the liver by CC chemokine receptor (CCR)-5/7 dependent trafficking.139,140 This observation has relevant impact on antitumor immunity as DCs could efficiently prime antigen-specific immune responses. Immune-stimulatory DCs typically express MHC class I/II along with costimulatory molecules (CD40, CD80, CD83, CD86) and release Th1-cytokines (IL2, IL12, IL23, and type I interferons).101,141 However, hepatic DCs include lineage subsets that only cause partial T-cell activation and may lead to local tolerance. Hepatic DCs hereby represent a mixture of activating and dysfunctional DC subtypes, which show very distinct activation competency if analyzed separately.142,143 Minimal T-cell activation by a mixture of hepatic DCs indicates that the relative abundance of dysfunctional DC subtypes compared with activating DCs determines local tolerance.144,145 IL10 is capable to prevent DC maturation and increases with progressive tumor burden in the serum of

HCC patients. This may explain how immature DCs accumulate in the context of HCC.146 High frequencies of circulating immature DCs in HCC patients147 and lack of HCC-infiltrating activated DCs with CD83 expression148 support the concept of inhibitory DC composition in context of cancer.

Tumor-Associated Macrophages Tumor-associated macrophages are the most-versatile HCCassociated stromal cell population to have a major impact on anticancer immune responses. Their functional plasticity ranges from proinflammatory (classical) M1 macrophages to anti-inflammatory (alternative) M2 macrophages.149 M1 macrophages prime immune responses via IL6, IL12, and TNF-α secretion and present antigens via MHC molecules. In turn, M2 macrophages lack sufficient MHC expression and release anti-inflammatory factors, such as IL10, IL23, PGE-2, and TGF-β. During inflammatory resolution M2 macrophages provide growth factors (EGF, IGF, and VEGF) and matrix metalloproteinases (MMP), which promote tissue regeneration or remodeling. Along with functional macrophage polarization their phenotypic marker composition changes (M1: CD68, HLA-DRhigh vs. M2: CD163, CD203, and HLA-DRlow).149 Tumor-associated macrophages are generally regarded as negative prognostic marker for HCC due to their immunemodulatory and growth promoting properties. Hence, CD68þ macrophage densities in resected HCC are inversely correlated with overall survival.150 However, high CD68þ macrophage densities in conjunction with tumor-infiltrating memory CD45ROþ lymphocytes indicated a better overall survival after HCC resection.151 In addition, macrophages are capable to eliminate opsonized tumor cells and execute senescent cell deletion.47,152,153 These conflicting data highlight the importance of alternative TAM polarization, which Seminars in Liver Disease

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Immune Control in Hepatocellular Carcinoma Development and Progression: Role of Stromal Cells

Immune Control in Hepatocellular Carcinoma Development and Progression: Role of Stromal Cells determines HCC prognosis. Assessment of CD163þ TAMs densities eventually confirmed the predominant M2 polarization in resected HCCs, which was associated with reduced overall survival.154 Increased shedding of soluble CD163 (sCD163) into the bloodstream of HCC patients during tumor progression supports the polarization theory.155 The M2 polarization of TAMs is maintained by colony stimulating factor-1 (CSF-1) and IL4, which are both highly expressed in HCC tissue.48,156 CSF-1 functions as central macrophage maturation factor, whereas IL4 augments M2 polarization.157 Recently, lactate has also been identified as a fundamental M2 polarization stimulus in hypoxic tumor tissue,158 which likely affects TAM polarization in HCC showing critical perfusion. Along with polarization, TAMs are activated by LPS and apoptotic bodies present in the HCC environment, which induces secretion of immune-modulatory factors.159 Tumor-associated macrophages located in murine HCCs, for example, inhibit tumor-directed T cells by secretion of IL10, which induces PD-L1 expression on HCC-associated monocytes.160 Alternative macrophages further produce anti-inflammatory TGF-β and PGE-2 upon stimulation.161 Macrophages are capable to produce arginase and IDO to suppress T-cell functions162,163 and release VEGF in context of inflammatory stimuli, which activates regulatory T cells via VEGF-receptor 2.126 In a murine ovarial cancer model, TAMs recruit regulatory T cells to the tumor via CCL22,132 a chemokine axis also activated in hepatitis B associated HCC.133 MMPs expressed by TAMs show additional immune modulatory activity. Elevated sCD163 serum concentrations in HCC patients indicates involvement of the proteinase ADAM17, which is responsible for sCD163 shedding during macrophage activation.164 ADAM17 activation potentially affects HCC and inhibits NK-cell induction by cleavage of the activating NKp30 ligand B7-H6. 165 In addition, HCC-associated TAMs express MMP9, 166 an enzyme able to shed NK-cell-inhibiting MICA fragments from tumor cells.167

Myeloid-Derived Suppressor Cells Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous cell population with monocytic or granulocytic morphology, which share immune-suppressive functions. MDSCs represent a stromal component of different tumor entities and suppress T-cell function by arginase-1, nitric oxide, and ROS production.138 Human MDSCs typically express myeloid-lineage markers (CD33, CD11b) and lack relevant MHC class II HLA-DR expression. In mice, MDSCs are characterized by myeloid GR1 and CD11b expression. The intermediate maturation state of MDSCs leads to phenotypic plasticity and allows maturation into DCs and macrophages in monocytic subsets.138 MDSCs with a CD14þ/HLA-DR/low phenotype have been isolated from resected HCC tissue.168 These monocytic MDSCs inhibit T-cell responses directly by production of arginase-1 or via regulatory T-cell activation. Interestingly, CD14þ/HLA-DR/low MDSC did not secrete immune-modulatory TGF-β or IL10 ex vivo and were resistant to DC maturation stimuli, indicating a stable phenotype. CorreSeminars in Liver Disease

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lation of circulating MDSC frequencies with reduced recurrence-free survival after local HCC ablation supports the prognostic impact of this MDSC subtype.97 Another report describes a correlation between HCC stage an circulating MDSCs, which were defined by a Lin/CD33þ/HLA-DR/low phenotype.169 Reconstitution of T-cell function after combined Treg and MDSC depletion in PBMC obtained from HCC patients suggests a related immune modulation.170 However, nonselective depletion in this report did not allow assessment of specific MDSC function.

Regulatory T Cells Regulatory CD4 T lymphocytes (Treg) are the prototype of immune-suppressive cells, which inhibit antigen-specific T-cell responses. Tregs express activation markers (CD25, CD62L, and CD127), which are commonly found in chronically stimulated lymphocyte subsets without immunosuppressive function. The more-specific surface marker GARP and the transcription factor FoxP3 eventually define immunosuppressive Treg subtypes.171,172 Tregs activation involves specific antigen recognition by TCRs and cooperative IL10 and TGF-β signaling. Activated FoxP3þ Treg block effector T lymphocytes by direct cell-cell contact via inhibitory molecules, such as CTLA-4, Lag-3, and membranebound TGF-β. 173 Release of soluble IL10 and TGF-β contribute to inhibitory Treg function, but are not essential for effector T-cell inhibition in vivo. Interestingly, constitutive expression of CD25 (IL2 receptor) by Tregs deprives IL2 from the circulation, which impairs effector T-cell proliferation.173 These effects eventually suppress T-cell maturation, priming, and effector functions required for tumor control. First reports described CD4þ/CD25þ Treg accumulation in HCC, which inversely correlated with HCC infiltrating CD8þ T lymphocyte functions.174,175 Other studies identified elevated Treg frequencies in the blood circulation of HCC patients.96,170 As expected, Treg isolated from HCC patients broadly inhibited T-cell activation upon stimulation with anti-CD3/CD28 antibodies.96,174,175 Specific inhibition of tumor-directed T cells was confirmed by Treg depletion, which reconstituted T-cell responses against HCC-related AFP.50 The potent immunosuppressive Treg function translates into decreased overall survival of HCC patients with elevated circulating Treg frequencies96 and accounts for reduced overall survival after HCC resection.70 Several studies confirmed the impact of Tregs on HCC prognosis, which has been summarized by a recent meta-analysis.110

Perspective The summarized mechanisms of immune control and the corresponding stromal cell components clearly determine the clinical outcome of HCC (►Table 2). Therefore, reconstitution of local immune surveillance may provide a potent approach for HCC therapy.69 Following this concept, reconstitution of anticancer immune responses via vaccination has been pursued for a long time. However, vaccination approaches were hampered by impaired immune cell priming of tumor-directed effector T cells. Alternative introduction of tumor-directed

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Table 2 Impact of immune-regulatory stromal cells on hepatocellular carcinoma prognosis Cell lineage

Source

Clinical setting

Outcome

Reference

HCC

Resection

Increased OS

181,182

PBMC

NR

HCC Stage

146

Dendritic cells S100þ -

Lin CD11c

high

HLA-DR

þ

CD4þ CD25þ

PBMC

NR

Reduced OS

96

FoxP3

þ

HCC

Resection

Reduced DFS, OS

70,183,184

FoxP3

þ

HCC

Resection

Reduced OS

185

FoxP3þ

HCC

Resection

Reduced DFS

186

CD4þCD25þFoxP3þ

PBMC

Resection

Reduced DFS, OS

184

Macrophages, monocytes, and MDSCs CD68þ

HCC

Resection

Increased DFS, OS

151

CD68þ

HCC

Resection

Reduced DFS, OS

156,187

HCC

Resection

Reduced RFS, OS

154

þ

CD68 CD163 þ

CD68 PD-L1

þ

þ

HCC

Resection

Reduced DFS, OS

98,160

CD14þ TIE2þ

PBMC

Resection / local ablation

Reduced RFS

188

CD14þ HLA-DR-/low

PBMC

Local ablation

Reduced RFS

97

Abbreviations: DFS, disease-free survival; MDSCs, myeloid-derived suppressor cells; NR, not rated; OS, overall survival, PBMC, periphery blood mononuclear cells; RFS, recurrence-free survival.

T cells, which were specifically engineered to recognize and eliminate malignant cells also face some unresolved obstacles. This includes the basic choice of the optimal TAA target to avoid side effects. The narrow target spectrum of selected antigen-specific T cells bears the risk of tumor resistance by TAA downregulation or epitope evasion. Furthermore, the limited tumor infiltration of therapeutic T cells and the restricted T-cell expansion requires additional optimization. Particularly, the functional stability of therapeutic T cells is challenging, as activated T cells may undergo apoptosis or face functional inhibition/exhaustion in the tumor environment as outlined above. Modulation of inhibitory stromal cells provides an alternative approach for anticancer immunotherapy, which could support specific approaches by a broader mode of action. Reconstitution of suppressed tumor-directed immune responses is promising as T cells specific for several HCCassociated antigens have been confirmed.69 This could be achieved by immune-stimulatory cytokines or TLR-ligands, shifting the Th1/Th2 balance toward a local Th1 response. Early experiments of complete TAM depletion have been successfully introduced to improve treatment response in murine HCC models.176 More specific targeting of TAM polarization via nuclear-factor kappa B inhibition or CSF-1receptor blockage, were successfully tested in murine cancer models.177,178 Particularly, therapeutic CSF-1-receptor inhibition seems promising for the treatment of CSF-1 expressing HCC.48,156 Monoclonal antibodies targeting lymphocytic checkpoint molecules are currently the most promising approach for tumor immune therapy. Inhibitory PD-1/PD-L1 antibodies,

for example, activate antitumor T-cell responses in HCCbearing mice79 and reconstitute function of HCC-specific T cells isolated from HCC patients.75 CTLA-4 blocking antibodies showed similar immune-stimulatory activity71 and were tested in HCC patients with a good safety profile.179 Despite initial insights into the biology of HCC-associated stromal cells the immune-modulatory armamentarium for an effective tumor treatment is still limited. Hence, further research about the environmental tumor network is required to develop innovative HCC-directed immunotherapies.

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