TABLE 1.
The immune cells in TME: Effector T cells.
| Cells | The research direction | Result | Reference |
|---|---|---|---|
| CD8+ T cell | The immune mechanism | NanoMnSor enhances the efficacy of anti-PD-1 antibodies and whole cell cancer vaccine immunotherapy by reducing tumor invasion of hypoxia-induced tumor-associated macrophages, promoting macrophage polarization into an immune-stimulating M1 phenotype and increasing the number of CD8 cytotoxic T to reprogram the immunosuppressive TME. | Chang et al. (2020) |
| CD8+ T cell | immunotherapy | PVRL1 upregulated by HCC cells stabilizes PVR on the cell surface, which interacts with the inhibitory molecule TIGIT of CD8 effector memory T cells. It is possible to develop PVRL1/TIGIT inhibitors as well as anti-PD1 to treat HCC. | Chiu et al. (2020) |
| CD8+ T cell | Prognostic marker | PD1 or TIM3PD1 CD8 T cells were significantly associated with poor prognosis, and the latter were adjacent to PD-L1 tumor-associated macrophages. | Ma et al. (2019) |
| CD8+ T cell | immunotherapy | SFGL2 promotes HCC growth by reducing DC activity and subsequent cytotoxicity of CD8 T cells, suggesting that SFGL2 is a novel potential therapeutic target for HCC therapy. | Yang et al. (2019a) |
| CD8+ T cell | The immune mechanism | IL-35 inhibits the cytolytic and noncytolytic functions of CD8 T cells against non-viral hepatitis associated HCC, possibly inhibiting the expression of perforin. | Yang et al. (2019b) |
| CD8+ T cell | The immune mechanism | Suppression of the tumor immunosuppressive environment and immune escape is accompanied by proliferation of functional cytotoxic CD8 T cells as well as suppression of myeloid suppressor cells and regulatory T cells in the tumor environment. | Tao et al. (2019) |
| CD8+ T cell | The immune mechanism | A large number of TEM-1 positive (TEM-1) TAM in the late stage of HCC development indirectly impair the cytotoxic function of CD8 T cells and induce the apoptosis of CD8 T cells. | Wu et al. (2019a) |
| CD8+ T cell | immunotherapy | The Δ- catenin peptide vaccine stimulates the activation of cytotoxic T lymphocytes (CTL) and enhances the invasion of CD8+ T cells into the tumor. In addition, Δ- catenin peptide vaccine can enhance the secretion of IFN-γ and the killing effect of T cells on tumor cells. | Huang et al. (2018) |
| CD8+ T cell | The immune mechanism | Stat3-blocked lysates of whole HCC cells stimulated activation of T and natural killer (NK) cells and enhanced cytotoxic CD8 T cell infiltration in tumor tissues. | Han et al. (2017) |
| CD8+ T cell | The immune mechanism | Antibody against CD274(PD-ligand 1 [PD-L1]), TIM3, or LAG3 increases CD8 and CD4 TIL proliferation and cytokine production in response to stimulation by polyclonal antigens or TAA. | Zhou et al. (2017) |
| CD8+ T cell | immunotherapy | Tremelimumab in combination with tumor ablation is a potential new therapy for patients with advanced HCC, resulting in the accumulation of CD8 T cells in tumors. Positive clinical activity was observed and may replace HCV viral load. | Duffy et al. (2017) |
| CD8+ T cell | immunotherapy | PD-L1 upregulation is mainly induced by pre-existing activated CD8+ cytotoxic T cells in the HCC environment, rather than constitutively expressed by tumor cells, and is a favorable prognostic factor for HCC. | Xie et al. (2016) |
| CD8+ T cell | The immune mechanism | Expression of programmed death 1(PD-1) and programmed death ligand 1(PD-L1) correlated with CD3+ and CD8+ cell density and clinical outcome. High density of internal and peripheral CD3+ and CD8+ T cells and corresponding immune scores were significantly associated with lower recurrence rates and prolonged RFS. | Gabrielson et al. (2016) |
| CD8+ T cell | Prognostic marker | Crosstalk of NK and CD8 T cells in tumor microenvironment may benefit patient prognosis. The count of NK and CD8 T cells infiltrating in CRC tumors may provide useful prognostic information | Sconocchia et al. (2014) |
| CD8+ T cell | immunotherapy | In the tumor microenvironment of sorafenib treated mice, tumor-specific effector T cells were upregulated, while the ratio of CD8+ T cells expressing PD-1 and regulatory T cells (Tregs) was reduced. | Chen et al. (2014) |
| CD8+ T cell | The immune mechanism | In HLA-A2 transgenic mice, the CD8+ T cells producing IFN-γ and the cytolytic activity in vivo were significantly increased. | Chen et al. (2012) |
| CD8+ T cell | The immune mechanism | As the disease progresses from LC to HCC, the frequency of circulating PD-1 (+) CD8+ T cells increases. Tumor-infiltrating CD8+ T cells showed a dramatic increase in PD-1 expression. In vitro, CD8+ T cells induced PD-L1 expression on HCC cells in an IFN-γ dependent manner, thereby promoting APOPTOSIS of CD8+ T cells, while blocking PD-L1 reversed this effect. | Shi et al. (2011) |
| CD8+ T cell | immunotherapy | Strong TAA-specific CD8+ T cell response inhibited HCC recurrence. For patients with HCC following local therapy, induction of TAA-specific cytotoxic T lymphocytes should be considered with immunotherapy, such as peptide vaccine. | Hiroishi et al. (2010) |
| CD8+ T cell | Prognostic marker | Overexpression of HLA-G protein in HCC is an independent indicator of poor prognosis, especially in early disease. The combination of HLA-G expression and Tregs/CD8+ ratio increased the prognostic power of both variables. | Cai et al. (2009) |
| CD8+ T cell | immunotherapy | HCA661 peptides H110 and H246 are naturally processed in dendritic cells (DCs) and when applied to DCs, they are sufficient to induce autologous CD8+ T cells to initiate cytotoxic responses against HCA661(+) human cancer cells. | Pang et al. (2007) |
| CD8+ T cell | Prognostic marker | The combination of low intratumoral Tregs with high intratumoral activated CD8+ cytotoxic cells (CTL) is the balance of CTL and is an independent prognostic factor for improved DFS and OS. | Gao et al. (2007) |
| CD8+ T cell | Prognostic marker | Increased CD4 (+) CD25 (+) Foxp3 (+) Treg may impair effector function of CD8+ T cells, promote disease progression, and represent a potential prognostic marker and therapeutic target in HBV-associated HCC patients. | Fu et al. (2007) |
| CD8+ T cell | immunotherapy | The functionally detectable presence of M3 (271) specific CD8+ T cells in HCC patients makes M3 (271) a potential target for immunotherapy in these patients. CD8+ T cells that respond to both NY-ESO-1 and MAG-A3 antigens provide a theoretical basis for the use of a bivalent vaccine in HCC patients with tumors expressing both antigens. | Zhang et al. (2007) |
| CD8+ T cell | Prognostic marker | HCC patients showed significantly higher WT p53-specific memory CD8+ T cell frequency and stronger WT p53-specific CTL activity compared to healthy controls. Increased frequency and activity of P53 specific CD8+ T cells were associated with deletion of selective HLA-A2 alleles and decreased expression of co-stimulatory molecules in tumor cells. | Cicinnati et al. (2006) |
| CD8+ T cell | The immune mechanism | CD4+ CD25 + T cells in the peripheral region of HCC may play a key role in controlling the activity of CD8+ cytotoxic T cells, thus promoting the development of HCC. | Yang et al. (2006) |
| CD4+T cell | The immune mechanism | The C/eBPα/miR-7 axis negatively regulates CD4+T cell activation and function through MAPK4, thus orchestrating experimental AIH mice. | Zhao et al. (2020) |
| CD4+T cell | The immune mechanism | In vivo treatment with MYC ASO without control ASO reduced proliferation, induced apoptosis, increased senescence, and remodeled the tumor microenvironment by recruiting CD4+T cells | Dhanasekaran et al. (2020) |
| CD4+T cell | The immune mechanism | Tumor associated CD4/CD8 double positive T (DPT) cells were found to be rich in L region, with co-expression of PD-1/HLA-DR/ICOS/CD45RO, and showed high levels of IFN-, TNF- and -1 after PD stimulation. Enrichment of DPT and PD-1DPT in L region indicated a good prognosis. | Zheng et al. (2020a) |
| CD4+T cell | The immune mechanism | The recruitment of cytotoxic cells, namely terminally differentiated CD4+ and CD8+ T cells (TEFF), is impaired in the tumor, and the effector memory CD4+ T cells are more attracted in this region. | Chaoul et al. (2020) |
| CD4+T cell | The immune mechanism | Knockdown of DCR3 expression in HCC significantly restored the immunity of CD4+T cells. Inhibition of DCR3 expression may provide a novel immunotherapy approach to restore immunity in HCC patients | Zhu et al. (2019) |
| CD4+T cell | The immune mechanism | Activated CD4+T cells from HCC stimulate macrophages to produce C-X-C motif chemokine 10(CXCL10). CXCL10 binds to the CXC chemokine receptor 3 on B cells and signals them through extracellular signal-regulated kinases, making them plasma cells that produce IgG. | Wei et al. (2019) |
| CD4+T cell | The immune mechanism | In a study of mice with liver tumors, CXCR6 was found to mediate the removal of NKT cells and CD4+T cells from senescent liver cells. | Mossanen et al. (2019) |
| CD4+T cell | immunotherapy | Liver-specific MYC transgenic mice fed the MCD diet were induced. Blockage of CPT with the pharmacological inhibitor perhexiline reduced apoptosis of CD4+T cells in the liver and inhibited tumor formation in HCC. These results provide useful information for the potential targeting of the CPT family to salvage intrahepatic CD4+T cells and for immunotherapy to assist NAFLD-promoted HCC. | Brown et al. (2018) |
| CD4+T cell | immunotherapy | Tumor-infiltrating LY6G MDSCs from orthotopic liver tumors treated with sorafenib significantly induced CD4+T cells expressing IL-10 and TGF-β and down-regulated the cytotoxic activity of CD8 T cells. | Chang et al. (2018) |
| CD4+T cell | The immune mechanism | Antibody against CD274(PD-ligand 1 [PD-L1]), TIM3, or LAG3 increases CD8 and CD4 TIL proliferation and cytokine production in response to stimulation by polyclonal antigens or TAA. | Zhou et al. (2017) |
| CD4+T cell | The immune mechanism | Blockage of PD-L1 can restore IFNγ/TNF-α production in BTLAPD-1 tumor CD4+T cells, but partially inhibit the activation of BTLAPD-1 CD4+T cells. | Zhao et al. (2016) |
| CD4+T cell | The immune mechanism | CB2 inactivation reduces expression of T cell recruitment chemokines and inhibits liver T cell recruitment, including specific CD4+ T cells. | Suk et al. (2016) |
| CD4+T cell | immunotherapy | IFNγ enzym-linked immunodot assay demonstrated that they induced antigenicity of specific CD4+T cells in healthy donors or in HCC patients before and after GPC3-SP vaccine administration. The natural processing of these epitopes was demonstrated by the immune response of helper T cells to dendritic cells (DCs) loaded with GPC3. | Sayem et al. (2016) |
| CD4+T cell | The immune mechanism | TGF-β expression was upregulated in DEN induced HCC mouse model. TGF-β promotes the differentiation of Foxp3 (+) CD4 (+) T cells (Treg cells) in vitro. | Shen et al. (2015) |
| CD4+T cell | immunotherapy | Intra-tumor combined administration of SLC and anti-CD25 mAb significantly reduced the frequency of Treg and increased the number of CD8+ and CD4+ T cells in tumor sites, and also maximally inhibited the growth and invasion of HCC. | Chen et al. (2013) |
| CD4+T cell | Prognostic marker | The high expression of IL-17 and IL-17RE is a promising predictor of poor prognosis in HCC. The precursor capacity of the CD4+ T cells that produce IL-17 may be involved in cross-talk of different types of inflammatory/immune cells than in HCC. | Liao et al. (2013) |
| CD4+T cell | The immune mechanism | CD25-Foxp3-T cells with a CD127-IL-10 + phenotype can be induced in vitro from naive CD4 (+) T cells involving programmed cell death 1 ligand 1, immunoglobulin-like transcript4, and human leukocyte antigen G. | Kakita et al. (2012) |
| CD4+T cell | The immune mechanism | In vitro restimulation experiments and in vivo depletion studies have shown that both CD4+ and CD8+ cells contribute to antitumor activity. Using PBMC from healthy volunteers and patients with HCC, it was shown that ASPH stimulation led to significant development of antigen-specific CD4+ T cells. | Shimoda et al. (2012) |
| CD4+T cell | Prognostic marker | Lack of recovered CD19, CD3, CD8, and especially CD4+T cells is associated with poor survival in patients. | Carr and Metes, (2012) |
| CD4+T cell | immunotherapy | Tregs significantly increased the inhibition of CD8+ and CD4 (+) T cell proliferation and cytokine secretion, and increased numbers of circulating CD4 (+) CD25 (+) Foxp3 (+) Tregs and tumor-infiltrating Foxp3 (+) cells prior to cryoablation were associated with a higher risk of recurrence or progression in HCC patients after cryoablation. | Zhou et al. (2010) |
| CD4+T cell | The immune mechanism | MDSC exerts its immunosuppressive function by inducing CD4 (+) CD25 (+) Foxp3 (+) regulatory T cells in co-cultured CD4 (+) T cells. | Hoechst et al. (2008) |
| CD4+T cell | immunotherapy | CD4+ T cells killed gene-independent CT26 cells and even homologous HEPA1-6 cells. In mice treated with DC/BNL + IL-12, a large number of CD4+ T cells and MHC class II positive macrophages infiltrated the tumor tissue. | Homma et al. (2005) |
| CD4+T cell | The immune mechanism | TRAIL receptors on HCC cells were upregulated by 5-FU, and TRAIL on CD4 (+) T cells, CD14 (+) monocytes and CD56 (+) NK cells was induced by IFNα. | Yamamoto et al. (2004) |
| CD4+T cell | The immune mechanism | IFN-γ was produced by incubation with DC/MIH-2 from CD4 (+) T cells but not from CD8+ T cells of inoculated mice. Anti-IFN-γ antibody attenuated the cytotoxicity of spleen cells. Immunization of CD4 (+) T cells with DCs loaded with homologous HCC cells, which produce IFN-γ in response to HCC antigens, leads to activation of macrophages that kill liver tumor cells at an early stage. | Irie et al. (2004) |