5.3. Tumor-Associated Fibroblasts
In human HCC, M-MDSCs are enriched in the fibrotic livers surrounding the tumor area, and the expression of M-MDSC marker CD33 is positively associated with tumor progression and negatively associated with the survival rate of HCC patients
[48][68]. In mouse HCC models, M-MDSC enrichment in fibrotic livers increases tumor development, which is associated with the reduction in tumor-infiltrating lymphocytes. The increase in M-MDSCs in the fibrotic liver is triggered by activated HSCs through p38 mitogen-activated protein kinase (MAPK) signaling, which can be suppressed to inhibit the crosstalk between HSCs and M-MDSCs to result in the suppression of HCC growth
[48][68].
5.4. Epigenetic Regulation
Epigenetic regulation, such as DNA methylation, histone modification, and transcription by noncoding RNAs, influences liver physiology and pathology and impacts liver disease development
[49][50][71,72]. The increased expression of PHD finger protein 19 (PHF19), an epigenetic regulator, predicts poor prognosis in patients with HCC. Mechanistically, PHF19 regulates the cell cycle and DNA replication, and high PHF19 expression is positively associated with the infiltration of MDSCs and Th2 helper T cells
[51][73].
5.5. Gut Microbiota
The gut microbial components lipopolysaccharides (LPSs) can activate TLR4, a family member of pattern recognition receptors (PRRs), on HCC cells to regulate nuclear factor-κB (NF-κB) and MAPK signaling pathways, resulting in cancer cell proliferation
[52][74]. Activation of the NF-κB signaling pathway can also promote the invasion of HCC cells by regulating extracellular matrix (ECM) remodeling, the expression of degradation enzyme matrix metalloproteinases (MMPs), and epithelial–mesenchymal transition (EMT), as well as angiogenesis in the tumor microenvironment
[53][75].
6. Roles of MDSCs in Different Liver Diseases
6.1. Hepatocellular Carcinoma
Anti-liver cancer treatments can regulate the infiltration of MDSCs and their function. In mice with HCC, sorafenib treatment can inhibit HCC growth, which is associated with a decrease in immunosuppressive cells, including both MDSCs and regulatory T cells
[54][90].
Treatment with 5-fluorouracil (5-FU) can increase the infiltration of MDSCs to suppress the efficacy of anti-PD-L1 antibodies in mice with orthotopic HCC. Mechanistically, VEGF-A expressed by tumor cells through activation of peroxisome proliferator-activated receptor-gamma (PPARγ) stimulates MDSC expansion to suppress CD8
+ T cell function
[55][92]. Therefore, PPARγ antagonist treatment can resensitize tumor cells to anti-PD-L1 treatment.
6.2. Cholangiocarcinoma
.2. Cholangiocarcinoma
Depletion of tumor-associated macrophages by the anti-CSF1R (colony-stimulating factor 1 receptor) antibody failed to suppress murine CCA due to a compensatory infiltration of G-MDSCs with immunosuppressive features
[56][96]. In contrast, dual treatments with anti-CSF1R and anti-Ly6G antibodies can significantly improve the efficacy of anti-PD-1 therapy to increase the survival time of CCA mice
[56][96]. Fibroblast activation protein (FAP)-mediated progression of intrahepatic cholangiocarcinoma (ICC) can be abrogated by anti-Gr-1 antibody treatment, as FAP mediates the infiltration of MDSCs in ICC via inducing CCL2 expression to promote tumor progression and angiogenesis
[57][97].
6.3. Metastatic Liver Cancer
About 50% of patients with colorectal cancer will develop liver metastases. The frequency of CD14
+HLA-DR
−/low MDSCs has been shown to increase in patients with colorectal cancer metastasis, and these MDSCs contribute to forming the premetastatic niche and are associated with inhibition of T cell proliferation and poor prognosis
[58][98]. Intravascular infection of TLR9 agonist ODN2395 via the portal vein can significantly suppress tumor progression by regulating MDSC depletion and programming in mice with colon adenocarcinoma liver metastasis
[59][99].
6.4. Subcutaneous Liver Cancer
Artemisinin (ART), an antimalarial drug with tumoricidal and immunoregulatory properties, can induce MDSC apoptosis and inhibit their accumulation and immunosuppressive function in vitro. In vivo, treatment of ART at doses of 50 mg/kg and 100 mg/kg is able to significantly suppress tumor growth in mice with subcutaneous Hepa 1-6-induced hepatoma by reducing the frequencies of M-MDSCs and G-MDSCs
[60][100].
6.5. Liver Regenration
In solid organs of the body, only the liver can regenerate to return to the original ratio of organ-to-bodyweight
[61][101]. In the early stage of liver regeneration, MDSCs have unique transcriptional profiles that increase ROS production and angiogenesis, contributing to liver regeneration
[62][102].
6.6. Autoimmune Hepatitis
Liver X receptor alpha (LXRα)-deficient mice have an increased expansion of both PMN-MDSCs and M-MDSCs in the liver compared to wild-type mice, resulting in amelioration of concanavalin A (ConA)-induced hepatitis
[63][103]. Mechanistically, MDSCs from LXRα
−/− mice have lower expression of interferon regulatory factor 8 (IRF-8) with increased capabilities of proliferation and survival compared to MDSCs from wild-type mice
[63][103].
6.7. Alcoholic and Nonalcoholic Liver Diseases
In addition to hepatitis viral infection, MASLD and ALD are the most common chronic liver diseases that are able to induce liver cancer initiation and progression
[64][65][104,105]. The population of G-MDSCs (expressing CD11b
+Ly6G
highLy6C
int) was increased in the blood, spleen, and liver of alcohol-treated mice. G-MDSCs have a protective role at the early stage of alcohol-induced liver injury, as depletion of these cells can increase serum levels of liver injury enzymes alanine aminotransferase and aspartate aminotransferase, while adoptive transfer of G-MDSCs can ameliorate acute alcoholic liver damage
[66][42].
7. Summary
MDSCs, a heterogeneous population, mediate both innate and adaptive immune responses in liver homeostasis and injury. They are involved in the pathogenesis of most liver diseases, such as ALD, MASLD, hepatitis, liver fibrosis, cirrhosis, and HCC, by regulating the interaction with both liver parenchymal cells such as hepatocytes and nonparenchymal cells. MDSCs can be broadly divided into two populations: monocytic MDSCs (M-MDSCs) and polymorphonuclear or granulocytic MDSCs (PMN- or G-MDSCs). Hepatic infiltration and activation of MDSCs can be regulated by inflammatory chemokines (e.g., CXCL1 and CCL2) and cytokines (e.g., IL-6), tumor-associated fibroblasts, epigenetic factors, and gut microbiota during liver pathogenesis. Given all these factors can impact the infiltration, phenotype, and function of MDSCs, it is very hard to define a specific subtype of MDSCs in liver diseases. In addition, the population of MDSCs can also be changed in a model-dependent manner. A multi-omics study can be performed in each chronic liver disease to uncover the features of disease-specific MDSCs and potential gene or protein targets for liver disease treatment.
Overall, MDSCs play important roles in the progression of chronic liver disease by regulating both intrahepatic innate and adaptive immune responses. MDSCs are optional targets for the treatment of primary and metastatic liver cancer, liver generation, and autoimmune hepatitis. However, only a few drugs are under evaluation for their therapeutic efficacy and potential synergistic effects with other treatments. Therefore, new medicines or strategies that can regulate the function and migration of MDSCs are needed.