Protein Arginine Methylation: An Emerging Modification in Cancer Immunity And Immunotherapy Part2

3.2.3 PRMT and Cyclic GMP-AMP Synthase(cGAS)- Stimulator of Interferon Genes (STING) Pathways

The cGAS-STING pathway is the most compelling activation pathway in tumor innate immunity (151). In melanoma tumor cells, CARM1 ablation induced dsDNA breaks and cGASSTING activation, together with the increased expression of several ISGs, including Irf7, Ifit1, Oasl1, and Tap1, and the enhancement of tumor cell susceptibility to cytotoxic T cells (79). MED12 and TDRD3 are CARM1 effector molecules, which promoted ISG expression, possibly because CARM1 catalyzed MED12 methylation at R1899 which in turn interacted with TDRD3 to facilitate its recruitment. TDRD3 is normally tightly bound to the topoisomerase TOP3B, with the TDRD3-TOP3B complex recruited to the promoter via H3R17me2a marks catalyzed by CARM1, to ultimately promote gene expression (79, 135, 152). A study on IFI16/IFI204 methylation in melanoma reported that PRMT5 methylated R12 in the PYRIN (protein-protein interaction) domain of IFI204 via a PRMT5-SHARPIN interaction, which attenuated IFI204 binding with dsDNA, restrained dsDNA-stimulated activation of cGAS/ STING signaling, and limited subsequent IFN-b and chemokine production by the TBK1-IRF3 pathway (19). It was reported that the PRMT5-MEP50 complex directly interacted with cGAS and catalyzed the R124 dimethylation of cGAS (153). The arginine methylation of cGAS impaired cGAS-DNA binding attenuated cGAS activation and inhibited cGAS-STING pathway-mediated type I IFN production, and this enzyme activity-dependent process was rescued by the PRMT5-specific inhibitor, EPZ015666 or PRMT5 specific small interfering RNAs (153) (Figure 5). Beyond its well-established role as a general cytosolic DNA sensor, nuclear cGAS has a noncanonical role in response to RNAs via PRMT5 recruitment. Specifically, nuclear-localized cGAS facilitated PRMT5 nuclear translocation and its subsequent recruitment to Ifnb and Ifna4 enhancers in a cGAS-dependent manner. PRMT5 then catalyzed the symmetric dimethylation of H3R2me2s to facilitate IRF3 access, thereby enhancing type I IFN production (154).

PRMTs may also regulate downstream TBK1-IRF3 signaling via direct interactions. PRMT1 was implicated in TBK1 and IRF3 phosphorylation, IRF3 dimerization, and nuclear translocation. PRMT1 catalyzed TBK1 arginine methylation at R54, R134, and R228 positions, thereby promoting its oligomerization and transautophosphorylation. The arginine methylation of TBK1 enhanced its kinase activity, resulting in subsequent type I IFN production, an effect independent of the K63-linked ubiquitination of TBK1 (155). Moreover, PRMT6 regulated IFN-I production by inhibiting TBK1-IRF3 complex assembly rather than TBK1 activity. The N-terminal domain of PRMT6 is bound to IRF3, blocking TBK1 and IRF3 interactions, thereby allowing PRMT6 to bind and isolate IRF3 in a manner independent of its methyltransferase activity (154). PRMT6 deficient cells showed enhanced TBK1-IRF3 interactions and subsequent IRF3 activation and type-I IFN production (156).

Additionally, reduced total sDMA levels selectively prevented type I and III IFN production by the context-dependent control of TCR-or PRR-stimulation-dependent transcription of IFNB1 and IFNL1, which was required for ISGF3 complex activation via the TBK1-mediated phosphorylation of the AP-1 transcription factors, c-Jun and ATF2 (157). PRMT1 mitigated the IFN function by interacting with the IC domain of the IFNa/b receptor IFNAR1 chain (158).

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3.3 PRMTs and Intrinsic Tumor Resistance Mechanisms

Increasing clinical evidence has identified the immunotherapy resistance associated with the activation of particular oncogenic pathways (159). Oncogenes orchestrate immune microenvironments by altering immune cell infiltration and the secretome of cancer cells, while several signaling pathways are involved in ICI resistance (6, 159). Given space limitations, we focus only on WNT/b-catenin, mitogen-activated protein kinases (MAPK), and phosphatase and tensin homolog (PTEN) pathways (Figure 6).

3.3.1 PRMTs Regulate the Wnt/b-Catenin Pathway

Blocking Wnt/b-catenin signaling elevated T cell-mediated cytotoxicity levels and boosted T cell infiltration into tumors, leading to complete regression when combined with immunotherapy in the majority of mice in a mouse model study (160). 

Consistent with non-T-cell-inflamed tumor studies, Wnt/b-catenin signaling drove immune exclusion and leukemia cells, PRMT5 activated Wnt/b-catenin signaling by increasing b-catenin and disheveled homolog 3 (DVL3) protein levels, which is an upstream positive b-catenin regulator. PRMT5 was recruited to the Dvl3 promoter and mediated H3R2me2s to activate Dvl3 transcription (165). PRMT5 also activated Wnt/B-catenin signaling by the direct epigenetic silencing of the pathway antagonists, AXIN2, WIF1, DKK1, and DKK3. The methylation markers H3R8me2a and H4R3me2a in Axin2, Wif1, Dkk1, and Dkk3 promoters, and subsequent Wnt/b-catenin signaling restrictions, were decreased in response to PRMT5 inhibition (166). Whereas, PRMT1-mediated methylation of Axin R378 decreased ubiquitination and enhanced Axin stability, which degraded cytoplasmic b-catenin (167). Thus, mounting data suggests arginine methylation exerts substantial and sophisticated roles in regulating Wnt/b-catenin signaling pathways.

3.3.2 PRMTs Regulate the MAPK Pathway

Several clinical studies reported that MAP/ERK kinase (MEK) and v-raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitors, in combination with anti-PD1 therapy, generated long-lasting tumor control due to relative increases in IL-6 and IL-10 expression, and tumor susceptibility to T cell cytotoxic effects (168–170).

MAPK pathway activation was increased in PRMT5 knockout tumor cells. PRMT5 reduced the duration and amplitude of epidermal growth factor (EGF)-mediated ERK activity, and decreased p‐Raf and p‐ERK phosphorylation levels (171, 172). The mono-methylation of epidermal growth factor receptor (EGFR) R1175 by the PRMT5-MEP50 complex in breast cancer favorably controlled its trans-autophosphorylation at Tyr 1173, resulting in endogenous SHP1 recruitment to attenuate son of sevenless (SOS) phosphorylation and ERK activation (173). Consistently, PRMT5 methylated CRAF at R563 which reduced CRAF stability and catalytic activity, thereby diminishing the amplitude of the ERK1/2 output in rat sarcoma (RAS) signaling (174). However, conflicting studies reported the role of PRMT5 in MAPK signaling, which was initiated by RAS-RAF-MEK-ERK stepwise phosphorylation. PRMT5 promoted fibroblast growth factor receptor 3 (FGFR3) expression, which in turn initiated ERK1/2 and PI3K signaling (175). PRMT5 catalyzed H4R3me2s in promoter regions to repress microRNA (miR)-99 transcription, and directly catalyzed the FGFR3 promoter which positively regulated FGFR3-mediated ERK1/2 and AKT activation (176, 177). Except for PRMT5, CRAF was also methylated at R100 by PRMT6, which altered CRAF-RAS binding potential and downstream MEK/ERK signaling activation (178).

3.3.3 PRMTs Regulate the PTEN-PI3K/AKT Pathway

PTEN deletion in melanoma promotes immune resistance, while PI3K-AKT-mTOR inhibitors enhance immunotherapy efficacy by modulating the TME, the mechanisms of which are not clearly understood but are multifactorial (179, 180). PRMT5 knockdown down-regulated PI3K/AKT/mTOR signaling in an influx of cancer cells, including bladder cancer, lymphoma, and Non-small-cell lung cancer (NSCLC) (181–183) 

Although links between PRMT5 and PI3K-AKT-mTOR signaling are ubiquitous in numerous cell types, it is unclear how PRMTs affect this pathway; do PRMTs regulate upstream proteins PTEN hypo-phosphorylation, or do PRMTs interact with PI3K/AKT/mTOR directly?

Several studies reported that PRMT5 and PTEN were linked; PRMT5 reduced PTEN mRNA and protein levels in glioblastoma neurospheres (GBMNS), which significantly increased AKT signaling (184). In gastric cancer, PRMT5 directly interacted with c-Myc to transcriptionally repress the expression of c-Myc target genes, including PTEN (138). The PI3K subunit, p55, directly interacted with MEP50 and was methylated by PRMT5 to activate PI3K/AKT signaling (185, 186). In terms of AKT, first, PRMT5 directly methylated AKT1 to promote its activation (187). Second, PRMT5-mediated methylation enhanced AKT mRNA translation, thereby facilitating AKT de novo synthesis, which was coordinated by the CITED2-NCL axis (188). Third, PRMT5 elevated AKT phosphorylation via the direct transcriptional repression of AXIN2 and WIF1 (166). Fourth, PRMT5 directly co-localized and interacted with AKT, albeit not with PTEN and mTOR; Akt phosphorylation at Thr308 and Ser473 and the downstream target GSK3 at Ser9 was markedly decreased without altering PTEN and mTOR phosphorylation at Ser2442 in PRMT5- deficient lung adenocarcinoma cells (183). Moreover, not only did PRMT5 up-regulate PI3K/AKT signaling, but PI3K/AKT in turn induced PRMT5 expression through the AKT-GSK3bMYC axis to form a positive-feedback loop (182).

The PI3K-AKT-mTOR pathway was likewise inhibited by other PRMTs. Asymmetrical dimethylation of PTEN R159 by PRMT6 decreased PTEN phosphatase activity and impeded the PI3K-AKT cascade (189). Also, PRMT2 inhibited estrogen receptor-a (ER-a) in breast cancer cells, resulting in the downstream suppression of PI3K/AKT and MAPK/ERK (190).

4 PRMTs AND IMMUNE CHECKPOINT THERAPY

Of the numerous immune checkpoints, the programmed death ligand-1/programmed death-1 (PD-L1/PD-1) signaling pathway is highly significant as it inhibits TCR-mediated T cell activation to regulate immune responses (191). Antigen-stimulated T cells express PD-1 which is a co-inhibitory receptor that interacts primarily with PD-L1/CD274. This promotes T lymphocyte apoptosis and lymphocyte death primarily by dephosphorylating TCR activation through the tyrosine phosphatase SHP2, thereby inhibiting downstream PI3K/AKT signaling and hindering cytokine secretion by T lymphocytes (191, 192). Moreover, sustained PD-1 signaling was shown to induce metabolic dysregulation that drove CD8+ T cell exhaustion (193).

PT1001B (a novel selective inhibitor of type I PRMTs) downregulated PD-1+ leukocytes and reduced PD-L1 expression in a pancreatic cancer mouse model, which significantly improved the inhibition of tumor cell proliferation and apoptosis induction when combined with anti-PD-L1 (194). PRMT1 knockdown in tumor cells and macrophages in a diethylnitrosamine (DEN)- induced hepatocellular carcinoma (HCC) mouse model generated significant decreases in PD-L1 and PD-L2, resulting in the reduced therapeutic efficacy of PD-1 antibody treatment (195). Moreover, the PRMT1 gene polymorphism rs975484 may serve as a predictive marker for response to PD-1/PD-L1 treatment (195). In mice implanted with MC38 murine colon adenocarcinoma cells, combining MS023 (a splicing modulator that inhibits type I PRMT enzymes) with PD-1 antibodies provided better therapeutic value (196). The combination of CARM1 inhibitors with CTLA4 or a PD-1 monoclonal antibody increased ICB efficacy in a melanoma mouse model as a result of the dual actions of CARM1 on T and tumor cells (79). As PRMT5 in tumor cells inhibited PD-L1 expression, GSK3326595 (PRMT5 inhibitor) and anti-PD-1 combination therapy was more effective than either treatment alone in murine xenograft liver tumors, an MYC-driven spontaneous HCC model, and murine melanoma models (19, 50). In B16 melanoma cells transfected with PRMT7 small interfering RNA or treated with the PRMT7 small molecular inhibitor, SGC30274, PD-L1 mRNA and protein levels were reduced, and ICI therapy potentiated. 

This observation could be attributed to increased H4R3me2s levels at the PD-L1 promoter modulated by PRMT7, but also improved IFN-induced PD-L1 expression, as PRMT7 also acted as an IRF-1 co-activator (48). Moreover, a “viral mimicry” response occurred after the up-regulation of endogenous retroviral element transcription, dsRNA expression, and stress granule formation due to diminished DNMT expression in the absence of PRMT7, thereby causing IFN activation and immune cell infiltration in B16F10 cells (48).

Numerous cytokines interact with PRMTs to maintain PD-L1 expression, the most efficient of which is IFN-g. IFN-g uses multiple pathways to induce PD-L1 expression in different tumor types, including JAK2/STAT1/IFR-1 pathways in gastric cancer, JAK/STAT3, and PI3K-AKT pathways in lung cancer, and MyD88-, TRAF6-, and MEK-dependent pathways in myeloma (197–199). PRMT activity inhibition blunted the IFN-g secretion (86, 200–202). PRMT1 also methylated the NFAT cofactor protein NIP45 to augment IFN-g production (90). In the TME of a PRMT5 knockdown transplanted tumor model, PD-1 and TIM3 expression and function were both inhibited in CD8+ T cells. PRMT5 inhibition suppressed STAT1 phosphorylation both in vivo and in vitro and was accompanied by decreased IFN-g production by T cells, and ISG transcription (200). One reason for this was that PRMT5 induced H3R2me2s marker enrichment in the STAT1 promoter region, between -1267 bp and -1094 bp, to enhance PD-L1 expression via the IFNg/JAK/STAT1 axis. The other reason was that PRMT5 bound to the PD-L1 promoter region between -792 bp and -671 bp, and directly activated its transcription via an unknown transcription factor (203).

5 CONCLUSIONS AND PERSPECTIVES

facilitate other modifications beyond their immediate targets. Specifically, key PRMT influences on the cancer immunity cycle and cancer immunotherapy have been demonstrated. PRMT5 restricted antigen processing and presentation in combination with inhibiting the cell surface expression of MHC I by modulating NLRC5 and IRF expression (19, 39, 45). Due to the conservation of catalytic sites, PRMT1, PRMT5, and CARM1, all promoted CXCL10 and CXCL11 transcriptional expression, while PRMT chemokine regulation was contextually relevant as PRMTs recruited different transcription factors at different stages during biological responses (56–60). PRMT-mediated histone posttranslational modifications have irreplaceable roles in initiating and activating T and B cells, TAM differentiation, the inhibitory effects of FOXP3+ Treg cells, and the induction of PD-L1 checkpoints. 

Additionally, PRMT-mediated chromatin remodeling contributed to the cytotoxic and depleted phenotypes of tumor-infiltrating CD8+ T cells. Therefore, PRMT inhibitors may be effective not just for ICB therapy, but also for alternative immunotherapies where T cells function as key effector cells, such as neoantigen-based cancer vaccines and chimeric antigen receptor T-cell therapies. Also, PRMT inhibition altered intrinsic tumor cell pathways, such as activating WNT-b catenin signaling to blunt T cell priming and recruitment, or suppressing PTEN to impair T cell-mediated killing, to indirectly regulate the immune microenvironment.

As methylation is a targetable modification, several studies have investigated the therapeutic potential of PRMTs in preclinical models, and their underlying associations with tumorigenesis in animal models. These studies established a rationale for using inhibitors against PRMT5 and type I PRMTs in clinical trials. 

Thus far, such inhibitors have been tested in patients with hematological or solid tumors (204). GSK3326595 is a selective PRMT5 inhibitor and was used in the METEOR-1 phase I study to investigate the safety, pharmacokinetics, pharmacodynamics, and efficacy of GSK3326595 in adults with solid tumors and nonHodgkin lymphoma. Critically, patients showed promising responses to therapy, and adverse events were prevalent but manageable (205). Furthermore, forthcoming research programs from this trial will include GSK3326595 and pembrolizumab combination therapy to investigate the efficacy of PRMT5 inhibitor and immunotherapy combination (205). 

In addition, another type I PRMT inhibitor, GSK3368715 (EPZ019997), induced anti-tumor effects over a broad range of hematological and solid tumor types, especially S-methyl-5’-thioadenosine phosphorylase gene (MTAP) -deficient tumors (NCT03666988) (204). Despite these advances, further investigations are required to address the many limitations, including potential toxicity over time, contrast targets or responses in specific cancer types, and compensatory mechanisms in PRMTs to improve all therapeutic modalities. Currently, only four PRMT inhibitor-based clinical cancer trials have been reported (https://www.clinicaltrials.gov/): PRMT1 inhibitor GSK3368715, and PRMT5 inhibitors GSK3326595, JNJ-64619178, and PF-06939999. While some clinical trials reported encouraging results, considerable uncertainty remains in terms of inhibitor safety, tolerability, pharmacokinetic profiles, and the combined therapeutic benefit of inhibitors and immunotherapy for cancer patients. Therefore, comprehensive pharmacokinetic and pharmacodynamic evaluations are required to maximize therapeutic efficacy while minimizing toxicity.

Overall, our understanding of PRMT functions and mechanisms in tumor immunity is in its infancy, however, several intriguing and critical questions require answers, 1) what are the epigenetic modification mechanisms associated with activated phenotypes in adaptive immune cells, 2) what is the immunological relevance of crosstalk between PRMTs, 3) what are their regulators, co-activators, targets, and molecular interactions, and 4) how do we integrate PRMT inhibitors with immunotherapies to achieve maximal and permanent therapeutic effects for cancer patients. Technological developments such as CRISPRCas9-based screens to identify immunological-related genes, and transcriptome single-cell sequencing of tumor-infiltrating immune cells may shed light on how PRMTs regulate TME phenotypes and function, which typically has been limited to small molecule inhibitors or transgenic mouse models rather than the genome-scale screening of primary immune cells. 

Similarly, next-generation sequencing technologies and small molecule inhibitor therapies, with improved specificity and affinity, will undoubtedly refine our understanding of arginine methylation mechanisms in unraveling antitumor immunity in different tumor types at different clinical stages.

PRMT inhibitors may function as a double-edged sword; they may selectively enhance or severely interfere with key aspects of antitumor immune responses, with unknown impacts on therapeutic success. Therefore, in developing cancer-specific therapeutic strategies for reprogramming immune responses against PRMT targets, careful rational drug combinations, and regimens are required in combination with innovative multi-target strategies that circumvent adaptive resistance mechanisms. This way, we can improve the prognosis of multiple cancers, especially those that are immunotherapy negative.

AUTHOR CONTRIBUTIONS

WD, JZ, SL, FT, CX, and ZW designed and wrote the article. FH, QL, ZY, JG, and YG critically revised the article. All authors contributed to the article and approved the submitted version.

FUNDING

This study was supported by the National Natural Science Foundation of China (grant nos. 81773236, 81800429 and 81972852), the Key Research & Development Project of Hubei Province (grant no. 2020BCA069), the Nature Science Foundation of Hubei Province (grant no. 2020CFB612), the Health Commission of Hubei Province Medical Leading Talent Project, Young and Middle−Aged Medical Backbone Talents of Wuhan (grant no. WHQG201902), the Application Foundation Frontier Project of Wuhan (grant no. 2020020601012221), the Zhongnan Hospital of Wuhan University Talented Doctor Program (grant nos. ZNYB2021008), the Zhongnan Hospital of Wuhan University Medical Science and Technology Innovation Platform Program (grant nos. PTXM2022025), the Zhongnan Hospital of Wuhan University Science, Technology and Innovation Seed Fund (grant nos. znpy2019001 and znpy2019048) and the Translational Medicine and Interdisciplinary Research Joint Fund of Zhongnan Hospital of Wuhan University (grant nos. ZNJC201922 and ZNJC202007).

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Conflict of Interest:

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

The reviewer JZ declared a shared affiliation with the authors to the handling editor at the time of review.

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Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China, 2 Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital of Wuhan University, Wuhan, China, 3 Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, Wuhan, China, 4 Department of Thoracic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China, 5 Department of Biological Repositories, Zhongnan Hospital of Wuhan University, Wuhan, China, 6 Tumor Precision Diagnosis and Treatment Technology and Translational Medicine, Hubei Engineering Research Center, Zhongnan Hospital of Wuhan University, Wuhan, China