MicroRNAs with Multiple Targets of Immune Checkpoints, as a Potential Sensitizer for Immune Checkpoint Inhibitors in Breast Cancer Treatment
Abstract
Simple Summary
Abstract
1. Introduction
2. Method
3. Results
4. Discussion
4.1. Existing and Potential Immune Checkpoints in Breast Cancer
4.1.1. PD-1/PD-L1
4.1.2. CTLA-4
4.1.3. TIM-3
4.1.4. LAG-3
4.1.5. BTLA
4.1.6. IDO1, 2
4.1.7. TIGIT
4.1.8. PD-L2
4.1.9. B7-H6
4.2. Selected MicroRNA Targeted Multiple Immune Checkpoints in Breast Cancer
4.2.1. MiR-93-5p
4.2.2. MiR-149-3p
4.2.3. MiR-195/MiR-497
4.2.4. MiR-5119
4.2.5. MiR-138-5p
4.2.6. MiR-100-5p
4.2.7. MiR-200a
4.2.8. MiR-21-5p
4.2.9. MiR-4443
4.3. Oncogenice or Tumor Suppressor Roles of Selected MicroRNAs
4.4. Side Effect and Solutions
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
References
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MiRNA | Targeted Immune Checkpoints | Tumor Type | Experimental Setting | Functional Mechanisms | References | Number of Predicted Targets | Conserved Sites and Poorly Conserved Sites |
---|---|---|---|---|---|---|---|
MiR-93-5p | B7-H6, PD-L1, PD-L2 | Breast cancer, lung cancer, colorectal cancer | Database, in vitro, human sample | Reducing the expression of PD-1, PD-L1, PD-L2, and B7-H6 | [24,25,26] | 1385 | 2561 |
MiR-149-3p | PD-1, TIM-3, BTLA | Breast cancer | In vitro | Downregulating mRNAs for PD-1, TIM-3, and BTLA | [27] | 7852 | 17186 |
MiR-195/MiR-497 | PD-L1, B7-H6 | Breast cancer, diffuse large B cell lymphoma | Database, in vitro | Reducing the expression of PD-L1, PD-L2, and B7-H6 | [25,28] | 1515 | 2456 |
MiR-5119 | PD-L1, IDO2 | Breast cancer | In vivo, in vitro | Downregulating the expression of PD-L1 and IDO2 | [29] | 3078 | 2537 |
MiR-138-5p | PD-L1, PD-1, CTLA-4 | Breast cancer, oral squamous cell carcinoma | In vitro | Direct anti-tumoral effects and immunostimulatory effects by targeting PD-1 and CTLA-4 | [30,31] | 704 | 1093 |
MiR-100-5p | PD-L1, PD-1 PD-L2 | Breast cancer, bladder cancer | Database, human sample | Downregulating the expression of PD-1, PD-L1, and PD-L2 | [32,33] | 59 | 62 |
MiR-200a | PD-L1, PD-1 | Breast cancer, gastrointestinal cancer | Database, in vitro | Targeting PD-L1, PD-1, and CD86 | [33,34] | 905 | 1593 |
MiR-21-5p | PD-L1, PD-1, CTLA-4,LAG3 | Breast cancer, head and neck squamous cell carcinoma | Database, in vitro | Upregulating PD-L1, PD-1, CTLA-4, and LAG3 | [33,35] | 384 | 552 |
MiR-4443 | TIGIT, CTLA-4 | Lung cancer | In vivo, In vitro, database | Targeting TIGIT and CTLA-4 | [36,37] | 4481 | 6052 |
Ligand | Expression Location | Roles in Tumor Immunity | Potential Mechanisms | Approved Drugs or Candidates | Reference | ||
---|---|---|---|---|---|---|---|
Targeting Receptors | Targeting Ligands | ||||||
PD-1 | PD-L1/PD-L2 | Lymphocytes including T, B, and NK/NKT cells | Suppressing T cell activation and proliferation in late phase; inducing T cell apoptosis. | Phosphorylated PD-1-ITIM/SHP2/SAP signaling; TCR signaling inhibition | Pembrolizumab (approved); pucotenlimab (approved); RAPA-201 (phase I/II); nivolumab+ ipilimumab (phase II); ATRC-101-A01 +pembrolizumab (phase I) | Atezolizumab (Approved); Durvalumab (Approved); ATRC-101-A01 + Pembrolizumab (Phase I); DKY709 + PDR001 (Phase I) | [40,41,42,43] |
CTLA-4 | CD80/CD86 | Activated T cells | Inhibiting T cell activation in early phase | Phosphorylated CTLA4-YVKM/SHP2/RAS signaling; TGF-β/IDO inducing | Ipilimumab (approved); tremelimumab (approved); RAPA-201 (phase I/II); Nivolumab+ Ipilimumab (phase II) | NA | [44,45,46] |
TIM-3 | Galactin-9, CEACAM-1, HMGB1, PS | Tumor-infiltrating T cells, Tregs, DCs, monocytes, NK cells | Exhausting tumor-infiltrated T cells | Glycosylated TIM3/AKT/mTOR signaling; phosphorylated TIM3/NFAT/Bat signaling | Sabatolimab (phase III); MAS825 (phase III) RAPA-201 (phase I/II) | NA | [47,48] |
LAG-3 | MHC-II, galectin-3, LSECtin | Activated T cells, B, NK cells, DCs | Preventing CD4-MHC-II interaction; inhibiting CD4-dependent T cell function | Phosphorylated LAG-3-KIEELE/mediated reduction in calcium influx impairs TCR signaling | Relatlimab (approved); RAPA-201 (phase I/II) | NA | [46,49] |
BTLA | HVEM | T, B, NK cells, macrophages, DCs | Holding back T cell over-activation | Phosphorylated BTLA-ITIM/ITSM/SHP2; inhibiting both TCR and CD28 signaling | Icatolimab (phase II) | NA | [50,51,52] |
IDO1/2 | AhR | Tumor cells, stromal cells, and immune cells in TME | Inhibiting the function of effector T cell and promoting Tregs; inducing T cell apoptosis | Catalyzing the oxidative cleavage of tryptophan; producing metabolite kynurenic acid | Epacadostat (phase II); epacadostat and pembrolizumab (phase I/II) | NA | [53,54,55] |
TIGIT | CD155, CD112, CD113 | T cells, Tregs, NKT cells | Inhibiting NK/CD8+ T cell-mediated tumor killing; affecting CD8+ T cell priming and differentiation; inducing immunosuppressive DCs | TIGIT/PVR/IL-10 and TGF-β signaling; TIGIT/CD155 ERK signaling | Tiragolumab (phase III); vibostolimab (phase III); ociperlimab (phase III) | NA | [56,57] |
B7-H6 | NKp30 | Tumor cells | Regulating the T cell-mediated immune response | Helping NK cells to recognize abnormal cells | NA | NA | [58] |
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Zhou, H.; Jia, W.; Lu, L.; Han, R. MicroRNAs with Multiple Targets of Immune Checkpoints, as a Potential Sensitizer for Immune Checkpoint Inhibitors in Breast Cancer Treatment. Cancers 2023, 15, 824. https://doi.org/10.3390/cancers15030824
Zhou H, Jia W, Lu L, Han R. MicroRNAs with Multiple Targets of Immune Checkpoints, as a Potential Sensitizer for Immune Checkpoint Inhibitors in Breast Cancer Treatment. Cancers. 2023; 15(3):824. https://doi.org/10.3390/cancers15030824
Chicago/Turabian StyleZhou, Huiling, Wentao Jia, Lingeng Lu, and Rui Han. 2023. "MicroRNAs with Multiple Targets of Immune Checkpoints, as a Potential Sensitizer for Immune Checkpoint Inhibitors in Breast Cancer Treatment" Cancers 15, no. 3: 824. https://doi.org/10.3390/cancers15030824
APA StyleZhou, H., Jia, W., Lu, L., & Han, R. (2023). MicroRNAs with Multiple Targets of Immune Checkpoints, as a Potential Sensitizer for Immune Checkpoint Inhibitors in Breast Cancer Treatment. Cancers, 15(3), 824. https://doi.org/10.3390/cancers15030824