Introduction
Tumor-associated macrophages
Molecule | Target cell | Therapeutic setting | Major effects | Reference |
---|---|---|---|---|
CCR2 | TAMs | CCR2 antagonist | Inhibits the recruitment of inflammatory monocytes, infiltration and M2-polarisation of TAMs | [34] |
CCR2 | TAMs | Anti-CCR2 | Promotes epithelial‑to‑mesenchymal transition by upregulating matrix metalloproteinase‑2 | [35] |
CCR2 | TAMs | CCR2 monoclonal antibody | Inhibits recruitment of monocytes | [36] |
CSF-1 | TAMs | CSF-1 receptor antagonist | Reprograms polarization of TAMs | [37] |
IL-6 | TAMs | Anti-IL-6 | Blocks downstream effect of TAM products | [38] |
IL-6 | MDSCs | Anti-IL-6 | IL-6 expression levels strongly correlate with an MDSC phenotype and chemotherapy response in HCC patients | [44] |
chemokine (C-C motif) ligand 26 | MDSCs | Blockade of chemokine (C-C motif) ligand 26 | Knockdown of chemokine (C-C motif) ligand 26 in cancer cells profoundly reduces MDSC recruitment, angiogenesis, and tumor growth | [45] |
SSAO | MDSCs | SSAO inhibitors | May have an anti-tumor effect on HCC by inhibiting recruitment of CD11b+ and Gr-1+ cells and hindering angiogenesis | [46] |
STAT3 | MDSCs | Anti-STAT3 | Inhibiting STAT3 can enhance the clinical efficacy of CAR-T cells in LM through modulation of L-MDSC | [47] |
CCRK | MDSCs | Anti-CCRK | Hepatic CCRK induction in transgenic mice stimulates mTORC1-dependent G-csf expression to enhance polymorphonuclear MDSCs recruitment and tumorigenicity in HCC | [48] |
CCL9/CCR1 | MDSCs | Blockade of CCL9/CCR1 | CCL9 secreted by splenic macrophages induces a CCR1‑dependent accumulation of MDSCs in the spleen in a murine H22 hepatoma model | [49] |
ENTPD2/CD39L1 | MDSCs | Blockade of ENTPD2/CD39L1 | Hypoxia induces the expression of ENTPD2 on cancer cells leading to elevated extracellular 5'-AMP, which promotes the maintenance of MDSCs by preventing their differentiation in HCC | [50] |
PD-L1 | MDSCs | PD-1 monoclonal antibody | PD-L1+ MDSCs could be used as a new biomarker of HCC | [51] |
IL-18/TLR2 | MDSCs | Blockade of IL-18/TLR2 | IL-18 administration was sufficient to induce accumulation of MDSC, whereas hepatocyte-specific silencing of IL-18 in TLR2(-/-) mice decreased the proportion of MDSC | [52] |
TGF-β/Axl/CXCL5 | TANs | Blockade of TGF-β/Axl/CXCL5 | The synergy of TGF-β and Axl induces CXCL5 secretion, causing the infiltration of neutrophils into HCC tissue. | [72] |
cortisol | TANs | Inhibition of cortisol | increased cortisol production and TAN/TAM infiltration as primary factors in the gender disparity of HCC development in both fish and human | [73] |
CXCR2/CXCL1 | TANs | Blockade of CXCR2/CXCL1 | The CXCR2-CXCL1 axis can regulate neutrophil infiltration into HCC tumor tissues and might represent a useful target for anti-HCC therapies | [74] |
CXCL17 | TANs | Anti-CXCL17 | CXCL17 expression was associated with more CD68 and less CD4 cell infiltration | [75] |
CXCR6 | TANs | Anti-CXCR6 | Human HCC samples expressing high levels of CXCR6 contained an increased number of CD66+ neutrophils and microvessels | [76] |
miRNA-21 | CAFs | MiRNA-21 inhibitor | High level of serum exosomal miRNA-21 was correlated with greater activation of CAFs and higher vessel density in HCC patients | [84] |
CD24 | CAFs | Anti-CD24 | HGF and IL6 secreted by CAFs promoted the stemness properties of CD24+ HCC cells through the phosphorylation of STAT3 | [85] |
LOXL2 | CAFs | Anti--LOXL2 | The secreted LOXL2 promotes fibronectin production, MMP9 and CXCL12 expression and BMDCs recruitment to assist pre-metastatic niche formation | [86] |
PD-L1/IL6/STAT3 | CAFs | Blockade of PD-L1/IL6/STAT3 | HCC-CAFs regulate the survival, activation, and function of neutrophils within HCC through an IL6-STAT3-PDL1 signaling cascade | [87] |
IL6/STAT3 | CAFs | blockade of IL6/STAT3 | IL-6 secreted by CAFs promotes stem cell-like properties in HCC cells by enhancing STAT3/Notch signaling | [88] |
Keratin 19 | CAFs | Anti-Keratin 19 | Keratin 19 expression in HCC is regulated by Fibroblast-Derived HGF via a MET-ERK1/2-AP1 and SP1 Axis. | [89] |
LSD1 | CAFs | Anti-LSD1 | LSD1 Stimulates Cancer-Associated Fibroblasts to Drive Notch3-Dependent Self-Renewal of Liver Cancer Stem-like Cells | [90] |
PD-1 | Tregs | PD-1 monoclonal antibody | The ratio of CD4+CD127+ PD-1- T effector cells to CD4+Foxp3+PD-1+ Tregs was significantly increased following treatment with sorafenib | [114] |
PD-1 | Tregs | PD-1 monoclonal antibody | Sunitinib-mediated tumoricidal effect and Treg suppression synergized with antibody-mediated blockade of PD-1 to powerfully suppress tumor growth and activate anti-tumor immunity | [115] |
PD-1 | Tregs | PD-1 monoclonal antibody | Sorafenib treatment enhanced functions of tumor-specific effector T cells as well as relieved PD-1-mediated intrinsic and Treg-mediated non-cell-autonomous inhibitions in tumor microenvironment | [116] |
CTLA4 | Tregs | CTLA4 monoclonal antibody | Leptin inhibited Treg activation and function in vitro, demonstrated by lower expression of TGF-β, IL-10, CTLA4 and GITR in Tregs | [117] |
CTLA4 | Tregs | CTLA4 monoclonal antibody | Tumor-induced regulatory DC subset suppresses antitumor immune response through CTLA-4-dependent IL-10 and IDO production | [118] |
TIM3 | Tregs | TIM3 monoclonal antibody | Antibodies against TIM3 restore responses of HCC-derived T cells to tumor antigens, and combinations of the antibodies have additive effects | [119] |
Lnc-Tim3 | Tregs | Anti-Lnc-Tim3 | Lnc-Tim3 promotes T cell exhaustion, a phenotype which is correlated with compromised anti-tumor immunity | [120] |
TIM3 | Tregs | TIM3 monoclonal antibody | TIM3 -1516 G/T polymorphisms may affect the prognosis of HBV-related HCC and may be new predictors of prognosis for HCC patients | [121] |
TIM3 | Tregs | TIM3 monoclonal antibody | -1516G/T polymorphism in the promoter region of TIM3 gene may affect the disease susceptibility and HCC traits associated with HBV infection | [122] |
GITR | Tregs | GITR monoclonal antibody | Agonistic targeting of GITR can enhance functionality of HCC TIL and may therefore be a promising strategy for single or combinatorial immunotherapy in HCC | [123] |
GITR | Tregs | GITR monoclonal antibody | GITR-ligation and anti-CTLA-4 mAb can improve the antitumor immunity by abrogating Ti-Treg mediated suppression in HCC. | [124] |
ICOS | Tregs | ICOS monoclonal antibody | Regulatory T cells, especially ICOS+ FOXP3+ regulatory T cells, are increased in the HCCmicroenvironment and predict reduced survival | [125] |
OX40 | Tregs | OX40 monoclonal antibody | OX40 expression in HCC is associated with a distinct immune microenvironment, specific mutation signature, and poor prognosis | [126] |
LAG3 | Tregs | LAG3 monoclonal antibody | Antibodies against LAG3 restore responses of HCC-derived T cells to tumor antigens, and combinations of the antibodies have additive effects | [119] |
Marrow-derived suppressor cells
Tumor-associated neutrophils
Cancer-associated fibroblasts
Tumor-infiltrating Tregs
Antibody features | Antibody name | NCT number | Status |
---|---|---|---|
anti-CTLA4 | Ipilimumab | NCT03682276,NCT03510871,NCT03222076,NCT03203304 | Ongoing |
anti-CTLA4 | Tremelimumab | NCT01853618,NCT02519348,NCT02519348,NCT03298451, NCT02821754,NCT03482102, NCT03638141 | Ongoing |
NCT01008358 | Completed | ||
anti-PD-1 | Nivolumab | NCT01658878,NCT02576509,NCT03383458, NCT03682276, NCT03071094,NCT03382886, NCT03781960, NCT03033446, NCT03510871, NCT03299946, NCT03059147,NCT03630640, NCT03418922, NCT03655613,NCT02837029, NCT03785210, NCT03695250,NCT03655002, NCT02859324, NCT03439891 | Ongoing |
anti-PD-1 | Pembrolizumab | NCT02702401,NCT03062358,NCT03713593,NCT02658019, NCT03753659,NCT03006926,NCT03519997,NCT03337841, NCT03163992,NCT03397654,NCT03316872,NCT03099564, NCT02940496,NCT03419481,NCT03647163,NCT02509507, NCT03211416,NCT03347292,NCT03511222,NCT03095781, NCT03259867,NCT02595866, NCT02432963 | Ongoing |
anti-PD-1 | Tislelizumab | NCT03419897, NCT03412773 | Ongoing |
anti-PD-1 | Spartalizumab | NCT02988440,NCT02795429, NCT02947165,NCT02325739 | Ongoing |
anti-PD-1 | Camrelizumab | NCT02989922,NCT03463876,NCT02942329,NCT03722875, NCT03605706, NCT03793725,NCT03764293, NCT03601598 | Ongoing |
anti-PD-L1 | Durvalumab | NCT03298451,NCT03778957,NCT03482102,NCT02519348 NCT03638141,NCT03257761,NCT02821754,NCT02572687, NCT03539822 | Ongoing |
anti-PD-L1 | Avelumab | NCT03389126, NCT03289533 | Ongoing |
anti-PD-L1 | Atezolizuamb | NCT03170960,NCT03755791, NCT03434379 | Ongoing |