Table 1.
Epigenetic modifiers and microRNAs in improving the efficacy of ICB-therapy.
| RNA (m6A)-Modifiers (Editors/Erasers/Effectors) | |||||
|---|---|---|---|---|---|
| RNA Modifiers | Disease Condition | Target | Disease Mechanism | Therapeutic Strategies | Ref. |
| Writers Mettl3/14 | up-regulated in colorectal cancer and melanoma |
IFNγ, STAT1, IRF1, Cxcl-9 and Cxcl-10 | By reducing CD8+T-cells infiltrations in TME | CRISPR/cas9 silencing of Mettl3/14 via YTHDF2 | [8] |
| Mettl-3 | down-regulated in M1/M2-med. lung metastasis | Spred-2 | By recruiting immunosuppresive T-reg and MDSCs | Overexpressing Mettl3 via polarizing M1/M2-macrophages | [9] |
| m6A | m6A-mediated regulation of PD-L1 in HNSCC | G2M checkpoint and PI3K/AKT/ mTOR signaling | Analysed via cancer genome atlas TCGA and GSE65858 cohort | By targeting m6A regulatated signature genes | [10] |
|
Erasers FTO |
up-regulated in melanoma | PD-1, CXCR4 and SOX10 | Impairs anti-PD1 effect by reducing target gene expressions | Selective inhibition of FTO to enhance anti-PD1 effects | [11] |
| FTO | up-regulated in colon cancer | PD-L1 | Up-regulates PD-L1 expression in IFNγ signaling-independent manner | Selective inhibition of FTO inhibits PD-L1 to control colon cancer | [12] |
| ALKBH5 | up-regulated in melanoma | Mct4/Slc16a3 | By recruiting immunosuppresive T-reg and MDSCs | Anti-ALKBH5 enhances the effect of anti-PD1 therapy. | [13] |
|
Readers YTHDF1 |
up-regulated in solid tumors | Lysosomal cathepsins | Degrade neo-antigen and impair dendritic cell presentation | Anti-YTHDF1 suppress cathepsins and enhance DC cross-presentation | [14] |
| YTHDF2 | up-regulated in LGG (brain tumor) and several other immune cells | PD-1, CTLA4, TIM3 | Impair immune checkpoint signalling | Anti-YTHDF2 in combination with immunecheckpoint immunotherapy | [15,16] |
| DNA and Histone Modifiers in ICB-Therapeutics | |||||
| Epigenetic Regulators | Disease Condition | Target | Mechanism | Therapeutic Strategies | Ref. |
| DNA methylation | down-ragulates CTLA4 in HNSCC | CTLA4, CD28, CD80/86, ICOS | DNA methylation affects HNSCC | Selective DNA (DNMTs) inhibitors | [17] |
| DNA methylation | down-regulates PD-L1 in melanoma | Interfron signalling | cpG DNA methylation regulate melanoma | [18] | |
| DNA methylation | up-regulates PD-1 & CTLA4 in NSCLC | PD-1 (PDCD-1) CTLA4 |
Hypo-methylation increases PD-1, CTLA4 expression in NSCLC | Selective DNA (5hmC) inhibitors | [19] |
| DNA methylation | up-regulates PD-L1 & PD-L2 in HNSCC | PD-L1 (CD274) PD-L2 (PDCD1LG2) |
Hypo-methylation increases PD-L1 & PD-L2 expression | Combining DNA inh. with Nivolumab and Pembrolizumab | [20] |
| DNA methylation | up-regulates PD-L1 in CRC | PD-L1 (CD274) | DNA-methylation control PD-L1 exp. | Selective DNA (TETs) inhibitors | [21] |
| HDAC | up-ragulates CTLA4 in B-cell associated function | CTLA4 and LAG3 | Tcf1 regulate CTLA4 expression in TFH-cells | HDACi control CTLA4-mediated B-cell help | [22] |
| HDAC6 | up-regulates PD-L1 in melanoma | PD-L1 (CD274) STAT3 |
HDAC6 increase PD-L1 expression by recruiting STAT3 | HDAC6-inhibitor decreases PD-L1 by de-activating STAT3 | [23] |
| Active H3K4me3 | up-regulates PD-L1 in breast cancer | EMT-induced PD-L1 expression | Active H3K4me3 modifications in Breast cancer |
Selective histone inhi. enhance the efficacy of ICB-Abs | [24] |
| Active H3K4me3 | up-regulates PD-L1 in pancreatic cancer |
PD-L1 (CD274) | MLL1 catalyzed H3K4me3 to bind with PD-L1 promoter and increase its expression | MLL1 inhibitor in combination with anti-PD-L1,anti-PD-1 improves efficacy | [25] |
| Repressive H3K27me3 | down-regulates PD-L1 in HCC | PD-L1, IRF1 | EZH2 negatively regulate PD-L1 exp. by recruiting repressive H3K27me3 in HCC | Selective H3K27me3 inhibitor could enhance ICB efficacy | [26] |
| HDACi (Belinostat) |
up-regulates PD-L1 & CTLA4 in HCC | Increase IFN-γ & reduce T-reg populations |
Belinostat treatment increase anti-tumor immunity against HCC | Combining belinostat enhances the efficacy of ICB therapy | [27] |
| SAHA | Increases CTLA4 and Foxp3 exp. cardiac transplant | Foxp3 CTLA4 |
SAHA increases suppressive function of T-reg to prolong allograft survival | SAHA (HDACi) couls be a promissing immunosuppressive agent with CNI drug | [28] |
| H3Ac | up-regulates PD-L1 in drug resistant cancer cell | H3Ac enhance PD-L1 exp. | drug resistant issues in cancer cells | HDACi in combination with anti-PD-L1 | [29] |
| MicroRNAs in ICB-Therapeutics | |||||
| miRNAs | Disease Condition | Target | Mechanism | Therapeutic Strategies | Ref. |
| miR-15a,b miR-16, miR-193a-3p | down-regulated in MPM | Direct target of PD-L1 | miR-15a, miR-16 and miR-193a-3p (−)vely regulates PD-L1 | Respective miRNA mimics combined ICB-therapeutics | [30] |
| miR-17-5p | down-regulated in melanoma | Directly binds 3′-UTR PD-L1 |
miR-17-5p (−)vely regulates PD-L1 | miR-17-5p mimics with anti-PD-L1 Abs | [31] |
| miR-18a (miR-140, 142, 340, 383) | up-regulated in cervical cancer | PI3K/AKT, WNK2, SOX6, p53 PTEN, MEK | miR-18a (+)vely and miR-140, 142, 340, 383 (−)ly regulates PD-L1 | Respective miRNA antagomiR & mimics with ICB-therapy | [32] |
| miR-20b-21-130b | up-regulated in colorectal cancer | PTEN, B7-H1 (PD-1) |
miRs (+)vely regulates B7-H1 (PD-1) exp. | Respective miRNAs AntagomiRs in combination with ICB-therapeutics | [33] |
| miR-21 (CD4+T-cells) | up-regulated in arthritis and GC | PDCD4, Th17, STAT5, T-reg | miR-21 (−)vely regulates PDCD4, PD-1 | [34,35] | |
| miR-23a-3p | up-regulated in (MΦ) liver cancer | PTEN, AKT pathways | miR-23a-3p (+)vely regulates PD-L1 exp. | Anti-miR-23a-3p (antagomiR therapy) with anti-PD-L1 Abs | [36] |
| miR-25-93- 106b cluster | down-regulated in pancreatic cancer | CXCL12, PD-L1 | miR-25-93- 106b−/− mice increases PD-L1 | miR-93, miR-106b mimics with BET inh. | [37] |
| miR-28 | melanoma | PD-1 | miR-28 (−)vely regulates PD-1 | miR-28 mimics | [38] |
| miR-33a | down-regulated in Lung A. carcinoma | PD-L1,CTLA4, PD-1, CAND1 | miR-33a (−)vely regulates PD-1/PD-L1 | miR-33a mimics with combined ICB-Abs | [39] |
| miR-34a | down-regulated in AML, lymphoma | EBF-1 and 3′-UTR PD-L1 | miR-34a (−)vely regulates PD-L1 exp. | ICB therapy combined miRNA | [40,41,42,43,44] |
| miR-138-5p | down-regulated in CRC | Target 3′-UTR PD-L1 | miR-138-5p (−)vely regulatesPD-L1 exp. | miR-138-5p mimics combined ICB-Abs | [45] |
| miR-140 | down-regulated in NSCLC | miR-140/ PD-L1/cyclinE pathways | miR-140 target 3′-UTR PD-L1 (−)vely regulates its exp. |
miR-140 mimics with anti-PD-L1 therapy | [46] |
| miR-142-5p | down-regulated in pancreatic cancer | miR-142-5p target 3′-UTR PD-L1 | miR-142-5p (−)vely regulates PD-L1 exp. | miR-142-5p mimics + anti-PD-L1 therapy | [47] |
| miR-145 | down-regulated in ovarian carcinoma | Cisplatin cMYc (TcF) |
miR-145 (−)vely regulates PD-L1 exp. | miR-145 mimic (restoration therapy) with anti-PD-L1 Abs | [48] |
| miR-146a | up-regulated in melanoma | STAT1-IFNγ axis | miR-146a (+)vely regulates PD-L1 exp. | miR-146a antagomiR with anti-PD-L1 Abs | [49] |
| miR-148a -3p | down-regulated in dMMR/MSI-H CRC | miR-148a-3p binds to 3′-UTR PD-L1 | miR-148a-3p (−)vely regulates PD-L1 exp. | Respective miRNA mimics with anti-PD-L1 therapy | [50] |
| miR-155 | up-regulated in B-cell lymphoma | AKT and ERK | miR-155 (+)vely regulates PD-L1 exp. | miR-155 antagomiR + PD-L1 antagonists | [51] |
| miR-191-5p | down-regulated in colon-adenocarcinoma | PD-L1 | miR-191-5p (−)vely regulates PD-L1 exp. | miR-191-5p mimics | [52] |
| miR-195 | down-regulated in PC and DLBCL | PD-L1 | miR-191-5p (−)vely regulates PD-L1 exp. | miR-191 mimics | [53,54] |
| miR-197 | down-regulated in NSCLC | CKS1B/STAT3 (Bcl-2, c-Myc, CyclinD1) |
miR-197 (−)vely regulates PD-L1 exp. | miR-193 mimics (replacement therapy) + ICB-therapeutics | [55] |
| miR-200b, miR-152 | down-regulated in gastric cancer (GC) | B7-H1 (PD-1) | miR-200b and miR-152 (−)vely regulates B7-H1 | Respective miRNA mimics combined PD-L1 antagonists | [43,56,57] |
| miR-214 | down-regulated in B-cell lymphoma (DLBCL) | miR-214 atrget 3′-UTR PD-L1 | miR-214 (−)vely regulates PD-L1 exp. | miR-214 mimic in combination with anti-PD-L1 Abs | [58] |
| miR-217 | down-regulated in laryngeal cancer | AEG-1 and PD-L1 | miR-217 (−)vely regulates PD-L1 exp | miR-217 mimics with anti-PD-L1 therapy | [59] |
| miR-324-5p miR-338-5p | downregulated in Mycobateria-responsive hedgehog sign | PD-L1, SHH signaling |
(−)vely regulate PD-L1 |
miRNA mimics | [60] |
| miR-340 | down-regulated in Cervical cancer | PD-L1 | miR-340 (−)vely regulates PD-L1 exp. | miR-340 mimics | [61] |
| miR-375 | down-regulated in HNSCC | JAK2 | Inhibits JAK2-STAT1 axis suppressing PD-L1 exp. | miR-375 mimics | [62] |
| miR-424 (322) | down-regulated in ovarian cancer | PD-1/PD-L1, CD80/CTLA4 | miR-424 (322) (−)vely regulates PD-1/PD-L1, CD80/CTLA4 exp. | miR-424 (322) mimics (restoration therapy) + ICB-therapeutics | [63] |
| up-regulated in Colon cancer | CD28, CD80 and CD86 | up regulated miR-424 impairs anti-tumor immunity | modified tumor-secreted EVs with miR-424 knocked down |
[64] | |
| miR-497-5p | down-regulated in RCC (ccRCC) | Cell proliferation | miR-497-5p (−)vely regulates PD-L1 exp. | miR-497-5p mimic with anti-PD-L1 Abs | [65] |
| miR-513 | cholangiocytes in response to C. parvum infection | B7-H1 (PD-1) | miR-513 (−)vely regulates PD-1 exp. | miR-513 mimics | [66] |
| miR-570 | down-regulated in gastric cancer | B7-H1 (PD-1) | SNP (polymorphism) disrupts miR-570- B7-H1 interactions | Restoration therapy combined ICB-Abs | [43,67] |
| miR-873 | down-regulated in breast cancer | PI3K/Akt, ERK1/2 pathways | miR-873 (−)vely regulates PD-L1 by binding to 3′-UTR | miR-873 mimics with PD-1/PD-L1 inhibitor | [68] |
| miR-3127-5p | up-regulated in NSCLC | pSTAT3 | Upregulates PD-L1 by suppressing p-STAT3 | Anti-miR-3127-5p (antagomiR therapy) | [69] |
| miR-3609 | down-regulated in breast cancer | PD-L1 | miR-3609 (−)vely regulates PD-L1 exp. | miR-3609 mimics | [70] |
| miR-4717 | down-regulated in HBV | PD-1 | miR-4717 (−)vely regulates PD-1 exp. | miR-4717 mimics | [71] |