Table 2 Representative molecules and signaling pathways mediated pro−/anti-tumor immunity of HCC
Cytokines/signaling molecules | Category | Description | References |
|---|---|---|---|
IL-1β | Pro-inflammatory cytokine | • A favorable factor for prolonged OS of HBV-related HCC patients • TAMs-secreted IL-1β in HCC contributes to HIF-1α stability, IL-1β/HIF-1α induce EMT and metastasis of HCC | |
IL-12 | Pro-inflammatory cytokine (anti-tumor immunity modulator) | • Promote cytotoxicity and IFN-γ production • Mediate CD4+ T helper cells transformation to Th1 phenotype, enhance cell based immunity • Up-regulate NKG2D related NKs anti-tumor immunity | |
IL-8 | Pro-inflammatory cytokine | • Trigger potent pro-inflammatory signals in HCC; promote HCC immune evasion and metastasis • Enhance HCC-related fibrosis and Tregs enrichment in tumor tissue | |
IL-10 | Inhibitory cytokine that involves in both innate and adaptive immunity in HCC | • Tolerogenic DCs/ FcγRIIlow/−B cells derived IL-10 induces hepatic tolerance by promoting T cell hypo-responsiveness • Suppress CD4+ T cells activity via CTLA-4-dependent manner • IL-10 production is associated with Foxp3+ Tregs accumulation in HCC • Accelerate HCC progression by mediating polarization of alternatively activated M2 macrophages | |
IL-6/STAT3 | Pro-inflammatory/carcinogenesis signaling | • Mediate MDSCs activation then result in immunosuppression • Up-regulate IL-10, IDO expression; down-regulate IFN-γ; induce T cells dysfunction and apoptosis | |
PD-1/PD-L1 | Immune checkpoint molecules | • Impairing anti-tumor immunity and promotes CD8+ T cells exhaustion and apoptosis • PD-1 over-expressed myeloid cells, such as DCs, suppress T cell responses in HCC | |
LAG3 | Immune checkpoint molecule | • Up-regulated on TAA-specific T cells • Significantly impairs CD4+ and CD8+ TILs functions in HCC | [112] |
CTLA-4 | Immune checkpoint molecule | • Mediates immunosuppression by inducing Tregs activity and IDO and IL-10 productions in DCs • Suppresses the proliferation of T cells | |
Tim3/Galectin-9 pathway | Immune checkpoint signaling | • Negatively regulates Th1-mediated immune responses • Mediates CTLs dysfunction and immunosuppressive responses in HBV-associated HCC • Fosters HCC development by enhancing TGF-β-mediated alternative activation of macrophages | |
VEGF, PDGF, HGF | Major growth factors in TME of HCC | • Enhance interactions between TAFs/HSCs and HCC cells • Mediates recruitment of immune inhibitory cells • Mediates other pro-inflammatory signals in TME (e.g. IL-6/STAT3 axis) • Promotes angiogenesis and immune evasion | |
IDO | Immunosuppressive modulator | • High level IDO expression is associated with poor prognosis and high recurrence rate in HCC patients; a potential target for HCC immunotherapy • Enhance regulation of immune responses, such as T-cell proliferation impairment, promotion of Tregs expansion • IDO derived from HSCs and CAFs impair cytotoxicity and cytokine production of NK cells • CD14+CTLA-4+ regulatory DCs derived IDO suppress CTLs response; cause NKs dysfunction in HCC anti-tumor immunity | |
SDF-1α/CXCR4 | A multiple signaling that mediates HCC immune evasion, progression and metastasis | • Enhance interactions between TAFs/HSCs and HCC cells • Facilitate MDSCs recruitment and generation, then results in immune evasion • Contribute to HCC fibrosis and hypoxia • Synergize with other stroma-derived cytokines (such as HGF, VEGF, TGF-β and so on), promoting HCC growth, angiogenesis, metastasis | [116] |
CXCL17 | 119-amino acid chemokine | • An independent factor that correlates with HCC regulatory immune cells infiltration • Predict poor prognosis of HCC | [70] |
CCL2(also named MCP-1) | Multifunctional factor | • Multiple cellular resources, including HSCs, hepatocytes, macrophages and so on • CCL2/CCR2 promotes regulatory cytokines release, M2-macrophages accumulation and polarization • Suppress cytotoxic CD8+ T lymphocytes anti-tumor responses • Facilitate TANs infiltration in HCC | [118] |
Hypoxia (HIF-1α) | Versatile modulator of TME and tumor immunotolerant state | • Promote recruitment of Treg, MDSCs. • regulate release of multiple chemokines and inflammatory factors; Activate transcription of C-C motif ligand 26, 28 (CCL26, CCL28) and interleukines (ILs). • contribute to immune tolerance and angiogenesis. | |
CXCL1/CXCR2 signaling | Immunosuppressive signaling axis | • Impair immune balance in TME of HCC. • Facilitate immune escape via increasing MDSCs recruitment and repressing infiltration of IFNγ+CD8+ T cells. | [121] |
CXCL5 | C-X-C motif chemokine | • Recruits more TANs infiltration and contributes to TANs-induced HCC immune evasion. | [55] |
CCL15 | Immunosuppressive signaling | • Serves as an independent factor for HCC prognosis and survival. • Recruit CCR1 + CD14+ monocytes infiltration, accelerate tumor proliferation and metastasis by activating STAT1/erk1/2 signaling. • Upregulate immune checkpoints (e.g. PD-L1, Tim3) and immune tolerogenic enzymes (e.g. IDO, ARG) | [122] |