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Table 1 Immune cell functions and alterations across the spectrum of healthy liver, fibrosis, and hepatocellular carcinoma

From: Immunotherapy in hepatocellular carcinoma: the complex interface between inflammation, fibrosis, and the immune response

Cell type Healthy Liver References Fibrosis and chronic inflammation References Hepatocellular carcinoma References
CD8+ T cell Provide protection against infection [32] Progressive dysfunction and exhaustion, PD-1 upregulation with chronic inflammation and viral infection [90] Anti-tumor antigen-specific responses detected; Progressive dysfunction and exclusion from tumors, upregulated exhaustion markers, low production of granzyme B and perforin, decreased proliferation [96, 98, 116, 124,125,126]
CD4+ Treg Antigen-specific tolerance; Readily expand following interaction with HSCs, Kupffer cells, and LSECs [25, 26, 37] Secrete IL-10 and TGFβ; Inhibit CD8+ T cell responses; Promote B cell activation and production of IgG through CD40-CD40L interaction [84, 85] Increased numbers of Tregs found within liver tumors; Suppress CD8+ T cell production of perforin and proliferation; Inhibit CD4+ effector T cell proliferation; Suppress NK function including cytotoxicity and IFNγ production [96,97,98, 107]
CD4+ Th cell Anti-microbial protective immunity; Regulators of pro- and anti-inflammatory signals [32, 37] Decreased numbers of naïve CD4+ T cells in circulation in cirrhotic patients; Increased numbers of Th17 cells, IL-17 can promote fibrosis via activation of stellate cells [37, 83, 87, 88] Elevated CD4/CD8 ratio predictive of recurrence free survival; Increased expression of PD-1 and CTLA-4, Decreased cytokine secretion in intra-tumoral CD4+ cells compared to peripheral blood CD4+ T cells [96, 99]
B cell Not well characterized, few B cells found in healthy liver [32] Role not as well-defined; found to be activated in chronic liver disease [85] Rarely found via IHC staining of liver tumors, IgA-producing cells suppress CD8+ T cells [94, 113]
TCRγδ T cell Recognition of peptide and non-peptide ligands; Innate-like and adaptive T cell protection from pathogens [33] Production of pro-inflammatory IL-17; Recruitment of CD8+ T cells and Th1 cells; Killing of HSCs; Promote monocyte differentiation into MDSCs [37, 86] Possible anti-tumor cytotoxicity [118]
Kupffer cell Induction of tolerance to commensal bacteria and food particles; Recruit Tregs; Recruitment and clearance of neutrophils; Stimulate T cell response to infection; Recruit and activate NK cells via IL-12 and cell:cell contact [23, 28, 34,35,36,37, 39, 63] Lose tolerogenic properties under inflammatory conditions; Secrete reactive oxygen species, TGFβ, PDGF, TNFα, and matrix metalloproteinases; Activate HSCs [23, 33, 61, 65] Protective against tumors via clearance of tumor cells; Suppression of T cell function via PD-L1 expression [38, 111]
MAIT cell Protection against bacteria; React to lipid antigens [37, 43, 44] Exhausted phenotype with upregulation of PD-1 and CTLA-4; Capable of activating HSCs [92, 93] Potential anti-tumor cytotoxicity; Excluded from tumors and found at higher frequencies in surrounding tissue [44, 96]
NK cell Anti-viral protection through cytokine production and cytotoxicity [28] Protect against fibrosis by killing of HSCs and production of IFNγ; Can induce liver injury by worsening inflammation [27, 28, 33] Cytotoxic to tumor cells; Impaired function (decreased granzyme and perforin, decreased cytotoxicity) and decreased in number in tumors and peripheral blood; Decreased expression of KIR2DL1 and KIR2DL3 [28, 94, 97, 100]
NK T cell Th1-like phenotype in the presence of IL-12; Th2-like phenotype in the presence of IL-7. Type I NK T cells: Activate neutrophils and HSCs, cause hepatocyte death. Type II NK T cells: Suppress pro-inflammatory signaling pathways. [28, 45, 46] Type I NK T cells: Activation of HSCs and neutrophils, production of IFNγ and IL-4 can worsen inflammation [45, 72] Type I NK T cells associated with tumor control; Impaired cytotoxicity, decreased expression of KIR2DL1 and KIR2DL3 [71, 100]
Hepatic stellate cell Express MHC I and II; Induce tolerance and anti-microbial immunity; PD-L1 expression leading to T cell apoptosis [23, 39] Differentiate to myofibroblasts; Secrete matrix metalloproteinases, extracellular matrix remodeling; Secrete IL-6, TNFα and TGFβ, Induce Th17 cells and Tregs [39, 59, 61, 65, 88] Induce MDSC and polarize monocytes to an immunosuppressive phenotype; Promote tumor growth [42, 64]
Liver sinusoidal endothelial cell Expression of MHC I and II; Activate CD4+ and CD8+ T cell responses; Induce tolerance via PD-L1 expression; Induction of Tregs [35, 39, 40, 50] Impaired antigen-processing and lower MHC II expression in the setting of fibrosis related to high levels of circulating endotoxin [41] Induce tolerance to tumor-derived antigens; decrease ability of dendritic cells to stimulate T cell responses [42, 47]
Bone marrow-derived monocyte, macrophage, and dendritic cell Promote tolerance to commensals and food particles; Stimulate T cell response to infection; More tolerogenic than activating in healthy liver [39, 47] Dysfunctional antigen presentation; Increased non-classical monocytes; Production of pro-inflammatory cytokines (TNFα, IL-6, IL-1) [41, 77, 78, 82, 83] Conversion to MDSC capable of suppressing effector T cells, inducing Tregs, and promoting tumor growth through pro-angiogenic cytokine production; Conversely, can control tumors via induction of antigen-specific T cell responses; Impaired ability to penetrate tumor tissue [23, 42, 47, 64, 104]