TABLE 6.
Tumor-promoting immune cells: Myeloid-derived suppressor cells.
| Cells | The research direction | Result | References |
|---|---|---|---|
| MDSCs | The immune mechanism | The heterozygous loss of SPTBN1 significantly upregulated the liver expressions of IL-1α, IL-1β and IL-6, and increased the proportion of myeloid inhibitory cells (MDSC) and CD4CD25Foxp3 regulatory T cells (Foxp3Treg) in liver, which promoted the occurrence of HCC in DDC-fed mice. | Lin et al. (2021) |
| MDSCs | The immune mechanism | MDSCs contribute to tumor progression under psychological stress, chronic binding stress significantly promotes the growth of HCC, and MDSCs are mobilized from bone marrow to spleen and tumor sites. Also, the β-adrenergic signaling cascade plays a key role in the mobilization and recruitment of MDSC under chronic confinement stress. | Cao et al. (2021) |
| MDSCs | immunotherapy | Icaritin blocks MDSC production by blocking the attenuation of EMH, thereby inhibiting the immunosuppressive effect of the tumor, thereby triggering an anti-tumor immune response. Therefore, Icaritin can be used as a new adjuvant or even as an independent therapeutic agent for the effective treatment of HCC. | Tao et al. (2021) |
| MDSCs | immunotherapy | PIWIL1 overexpressed HCC cells attract myeloid suppressor cells (MDSCs) to the tumor microenvironment. MDSCs consumption reduced the proliferation and growth of HCC tumors overexpressed by PIWIL1. Complement C3 induces the secretion of HCC cells through PIWIL1, mediates the interaction between HCC cells and MDSC by activating the P38 MAPK signal in MD38, and then initiates the expression of the immunosuppressive cytokine IL10. | Wang et al. (2021a) |
| MDSCs | immunotherapy | After tivozanib treatment, the baseline number or frequency of FOXP3treg, MDSC, and exhausted T cells decreased significantly more. This may help identify patients who may benefit from c-kit/SCF antagonism and provide guidance for improving the efficacy of tivozanib in combination with immunotherapy. | Kalathil et al. (2020) |
| MDSCs | The immune mechanism | CD8+ T cells, MDSCs, and M2 macrophages were particularly increased in the tumorigenic liver of NCoA 5 ± male mice. NCoA5 deficiency promotes a unique hepatic tumorigenetic microenvironment through p21WAF1/CIP1 overexpression, which metformin reverses. | Williams et al. (2020) |
| MDSCs | immunotherapy/The immune mechanism | HSC promoted migration of MDSC through the SDF-1/CXCR4 axis. Pretreatment of MDSC with CXCR4 inhibitors or injection of SDF-1 knockout HSC inhibited migration of MDSC to the spleen and liver of tumor-bearing mice. | Xu et al. (2019) |
| MDSCs | Prognostic marker | Patients with an increased T-effector/Treg ratio before treatment showed significant improvement in OS. ERK + FLT-3+ Treg and MDSCs were significantly reduced after sorafenib treatment. An increase in baseline Flt-3+ p-ERK + MDSC was associated with a patient survival benefit. Conclusion High baseline CD4+ T effector/Treg ratio may be an important biomarker for prognosis in HCC. | Kalathil et al. (2019) |
| MDSCs | immunotherapy | CCR2 antagonists inhibited the infiltration of TAM and MDSC and delayed tumor growth in tumors of mice expressing A3b and A3b. Mechanically, upregulation of A3B in HCC inhibs the global abundance of H3K27me3 and reduces the presence of H3K27me3 on the chemokine Ccl2 promoter by interacting with the multicomb repressor complex 2(PRC2), thus recruiting large amounts of TAM and MDSC. | Wang et al. (2019c) |
| MDSCs | immunotherapy | Activated HSC induces mononuclear intrinsic p38 MAPK signaling, which triggers enhancer reprogramming for M-MDSC development and immunosuppression. Treatment with p38 MAPK inhibitors eliminated HSC-M-MDSC crosstalk to prevent HCC growth. Combined with I-BET762 suppressed patient-derived M-MDSC, combined with anti-PD-L1 therapy synergically enhanced TIL, resulting in tumor eradication and prolonged survival in a fibrotic HCC mouse model. | Liu et al. (2020b) |
| MDSCs | The immune mechanism | RIP3 knockdown results in an increase in MDSCs and a decrease in interferon Δ- positive (IFN-γ) clusters of tumor-infiltrating lymphocytes (CD8) differentiated into 8 positive (CD8) cells in HCC tissue, thus promoting immune escape and HCC growth in immunologically competent mice. | Li et al. (2019b) |
| MDSCs | The immune mechanism | By down-regulating the expression of IDO1, the HS donor induced T effector cells and inhibited MDSCs, and effectively restricted the tumor development of H22 HCC tumor-bearing mice. | Yang et al. (2019c) |
| MDSCs | The immune mechanism | March-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAM) from the tumor microenvironment contribute to the suppression of the CD8 T cell response. | Liu et al. (2018a) |
| MDSCs | immunotherapy | Adoptive transfer of CIK to tumor-bearing mice induced an increase in inflammatory mediators (e.g., CX3CL1, IL-13) and tumor-infiltrating MDSC in the tumor microenvironment, and MDSCs effectively inhibited the cytotoxic activity of CIKs in vitro. In contrast, treatment with PDE5 inhibitors reversed MDSC inhibition by Arg1 and iNOS, while systemic treatment with PDE5 inhibitors prevented MDSC accumulation in the tumor microenvironment after CIK cell treatment and increased its anti-tumor efficacy. | Yu et al. (2019b) |
| MDSCs | The immune mechanism | RT/IL-12 significantly reduced the accumulation of tumor-infiltrating myeloid suppressor cells (MDSC) and its inhibitory function by reducing the production of reactive oxygen species | Wu et al. (2018) |
| MDSCs | 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. IL-6 protects LY6G MDSC against sorafenib induced cell death in vitro. The combination of anti-LY6G antibody or anti-IL-6 antibody and sorafenib significantly reduced the cell proportion of LY6G MDSCs in orthotopic liver tumors, enhanced the proliferation of T cells, and synergically improved the therapeutic effect of sorafenib. | Chang et al. (2018) |
| MDSCs | The immune mechanism | Tumor-infiltrating CD11BCD33HLA-DR MDSCs in HCC patients can effectively inhibit autologous CD8T cell proliferation. Concordant overexpression of CCRK and MDSC markers (CD11b/CD33) was positively associated with poorer survival. Hepatocyte CCRK stimulated the immunosuppressive CD11BCD33HLA-DR MDSC amplification of human peripheral blood mononuclear cells by up-regulating IL-6. | Zhou et al. (2018b) |
| MDSCs | The immune mechanism | In HCC, hypoxia induces the expression of ENTPD2 on cancer cells, leading to an increase in extracellular 5′-AMP, which in turn promotes MDSC maintenance by preventing its differentiation. | Chiu et al. (2017) |
| MDSCs | immunotherapy | The tumor suppressive effects of chemerin were associated with metastasis of tumor-infiltrating immune cells from myeloid suppressor cells (MDSC) to interferon-γ T cells and decreased tumor angiogenesis. | Lin et al. (2017) |
| MDSCs | The immune mechanism | TAF-derived cytokines (such as IL-6 and SDF-1A) can induce MDSC generation and activation, and then weaken the human anti-tumor immune response, thus creating favorable conditions for the development of HCC. | Deng et al. (2017) |
| MDSCs | immunotherapy | The frequency of MDSC before treatment is a prognostic factor for HAIC prevention of HCC. Patients with lower MDSC frequency also had significantly longer overall survival. | Mizukoshi et al. (2016) |
| MDSCs | immunotherapy | The frequency of MDSC increased significantly in HCC patients. It is associated with tumor progression, but not with liver fibrosis or inflammation. | Arihara et al. (2013) |
| MDSCs | The immune mechanism | The MDSC-mediated functional inhibition of NK cells mainly depends on NKP30 on NK cells. | Hoechst et al. (2009) |