Morten Frier Gjerstorff

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Frontiers in ImmunologyOPEN ACCESSEDITED BYZhimin Tao,Jiangsu University, ChinaREVIEWED BYSom G. Nanjappa,University of Illinois at Urbana-Champaign,United StatesStefania Canè,University of Verona, Italy*CORRESPONDENCEMorten Frier Gjerstorffmgjerstorff@health.sdu.dkRECEIVED 11 July 2023ACCEPTED 14 August 2023PUBLISHED 23 August 2023CITATIONGjerstorff MF (2023) Epigenetic targetingof myeloid-derived suppressor cells: timeto move into infectious diseases?.Front. Immunol. 14:1247715.doi: 10.3389/fimmu.2023.1247715COPYRIGHT© 2023 Gjerstorff. This is an open-accessarticle distributed under the terms of theCreative Commons Attribution License(CC BY). The use, distribution orreproduction in other forums is permitted,provided the original author(s) and thecopyright owner(s) are credited and thatthe original publication in this journal iscited, in accordance with acceptedacademic practice. No use, distribution orreproduction is permitted which does notcomply with these terms.TYPE OpinionPUBLISHED 23 August 2023DOI 10.3389/fimmu.2023.1247715Epigenetic targeting of myeloid-derived suppressor cells: time tomove into infectious diseases?Morten Frier Gjerstorff1,2,3*1Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University ofSouthern Denmark, Odense, Denmark, 2Department of Oncology, Odense University Hospital,Odense, Denmark, 3Academy of Geriatric Cancer Research (AgeCare), Odense University Hospital,Odense, DenmarkKEYWORDScancer, MDSC (myeloid-derived suppressor cell), chronic infection, epigeneticinhibitor, inflammationIntroductionEvidence overwhelmingly suggests that myeloid-derived suppressor cells (MDSCs)play a crucial role in the pathogenesis of multiple types of infections, including tuberculosis,staphylococcal infections, viral hepatitis, immunodeficiency syndromes, chronic parasiticinfections, and fungal disorders (1). Thus, there is pressing need to develop therapies thattarget these cells. DNMT inhibitors have demonstrated potential in cancer patients andpreclinical cancer mouse models by effectively removing MDSCs. Given these observations,DNMT inhibitors should be considered as a potential treatment option for persistentinfections in which MDSCs play a primary role, in addition to their role incancer treatment.Targeting MDSCs with DNMT inhibitors incancer treatmentDNAmethyltransferase (DNMT) inhibitors, particularly decitabine and azacitidine, havebeen used for decades in the treatment of hematopoietic malignancies and are now beingintensively investigated for their potential to treat solid cancers (2). These inhibitors target theenzymes responsible for adding methyl groups to DNA, which are known as DNAmethyltransferases (DNMTs). DNA methylation is a crucial regulatory mechanism forcontrolling gene expression that is often disrupted during tumorigenesis. DNMTinhibitors, such as guadecitabine and decitabine, has been found to restore normal geneexpression patterns in cancer cells, thereby reversing their oncogenic phenotypes. Besidestheir cancer cell-intrinsic effects, DNMT inhibitors have also shown promise in enhancinganti-tumor immune responses. They do so by counteracting the immune suppressive effect ofMDSCs. MDSCs are immature, bone marrow-derived myeloid cells that are mobilized andrecruited to the tumor microenvironment by inflammatory mediators produced within thefrontiersin.org01Gjerstorff 10.3389/fimmu.2023.1247715tumor, where they play a crucial role in development of cancerimmune resistance (3). MDSCs are divided into two subtypes:polymorphonuclear (PMN-) and mononuclear (M-) MDSCs.Although these subtypes are phenotypically and functionallydistinct, they suppress T-cells by common mechanisms (3). Theseinclude secretion of immune suppressive molecules, such as nitricoxide (NO), reactive oxygen species (ROS), arginase, TGF-beta andIL-10, and induction of regulatory T-cells (Tregs). Encouragingly,multiple preclinical cancer mouse models have demonstrated thatDNMT inhibitor treatment greatly reduces the recruitment ofMDSCs to the tumor microenvironment and thereby enhance anti-tumor T-cell immune responses and improve the efficacy of cancertreatment (4, 5). This effect has been attributed to the ability ofDNMT inhibitors to inhibit myelopoiesis in the bone marrow andMDSC expansion in the spleen (4). In addition, DNMT inhibitortreatment has been shown to change existing MDSC towards a lessimmune suppressive phenotype (5).While potently inhibiting tumor-associated excessive myeloid proliferation and systemic accumulationof MDSCs, DNMT inhibitors seem to have minimal effects on B- andT-cell populations (4). In fact, these drugs may increase activationand cytolytic activity of CD8+ T-cells (6).Targeting MDSCs in infectious diseasesMDSCs are also important regulators of the immune responseagainst infectious diseases. They can be of benefit to the host byreducing the activity of T-cells, natural killer cells, and other immuneeffector cells that contribute to the immune response to protect thehost from harmful overreactions of the immune system. On the otherhand, excessive MDSC activity can prevent the immune system frommounting an effective response, which can ultimately favor pathogenpersistence and contribute to unresolved chronic infections(Figure 1). For example, PMN-MDSCs have been found to expandin patients with sepsis, and their numbers correlate with diseaseseverity (7, 8). In mouse models, anti-inflammatory MDSCs werefound to be massively expanded during late stages of sepsis,contributing to bacterial growth, inhibiting T-cell function, andincreasing mortality (9, 10). Mobilization of MDSC during sepsisseems to be mainly linked to infection with gram-positive bacteria (8).MDSCs also play a role in the development of chronic bacterialinfections (1). In tuberculosis patients, MDSCs inhibit T-cellresponses and promote bacterial growth (11), while ablation ofMDSCs in tuberculosis mouse models improves disease outcomes(12). Excessive accumulation of MDSCs in the lungs of M.tuberculosis-infected mice enhances disease severity, indicatingthat MDSCs provide a niche for M. tuberculosis survival withinthe infected lungs (12). Recruitment of MDSCs into infected tissueshas also been reported in mice with Salmonella infection. In thesemice, MDSCs were found to suppress T-cell responses by NOproduction (13). Likewise, MDSCs seem to play a crucial role indevelopment of chronic Staphylococcus aureus infections, which iscommonly associated with orthopedic biofilm formation andprolonged infections. MDSC were found to contribute to induceimmune suppression and therapeutic resistance to this pathogenand depletion of MDSCs facilitated biofilm clearance (14).Frontiers in Immunology 02Viral pathogens, such as HBV, HCV, HIV and EB virus, oftendevelop chronic infections and MDSCs are increasingly beingrecognized as a contributor to immune suppression and viralpersistence (1). For instance, MDSCs were expanded in the bloodof patients with chronic HCV infection and these cells were shownto suppress T and NK cell anti-viral responses (15). Likewise,MDSCs may also play a negative role in HIV-induced immunedeficiency syndrome, which is associated with T-cell dysfunction(15). In these patients, peripheral expansion of arginase-producingMDSCs correlates positively with viral load and drops uponantiviral therapy (15). On the other hand, there is evidence thatMDSCs exert a protective role in chronic HBV infections, possiblyby maintaining immune tolerance in HBV patients to avoid hepatictissue damage (15).The expansion of MDSCs has also been observed in infectionscaused by various types of protozoa and helminths (16). However,the role of MDSCs in parasitic infections remains a topic of debate.In certain parasitic infections, such as nematode infections, theincreased presence of MDSCs has been shown to suppress T-cells,potentially contributing to the establishment of chronic infections(16). For example, in response to H. pylogyrus bakeri infection,MDSCs effectively inhibit CD4+ T-cell proliferation, leading to thesuppression of CD4+ Th2 responses and the promotion of chronicinfection (17). On the other hand, MDSCs seem to play a supportiverole in the immune defense against several protozoans, includingLeishmania major and Trypanosoma cruzi (18, 19). This beneficialeffect is attributed to the production of nitric oxide (NO) byMDSCs, which aids in parasite clearance, while also potentiallypreventing excessive inflammation.Similarly to parasitic infections, MDSCs also exhibit diverseroles in fungal infections. For instance, during infections caused byboth Aspergillus fumigatus and Candida albicans, MDSCs areexpanded. However, their impact differs, as they are protectiveagainst Candida albicans but not necessarily against Aspergillusfumigatus (20). Moreover, it has been observed that various speciesof Candida can induce different levels of MDSCs (21), indicating aspecies-specific response. Furthermore, in the context ofCryptococcus neoformans infection, MDSCs have been found toplay an immune suppressive role, primarily mediated by theproduction of arginase (22). This indicates that the precise role ofMDSCs in the defense against infections with parasites and fungi ishighly influenced by the specific pathogen involved.DNMT inhibitors for treatment ofinfectious diseasesThe growing recognition of MDSCs as key regulators of immuneresponse in both cancer and infectious diseases highlights thepotential of targeting these cells for therapeutic interventions. Theability of DNMT inhibitors to inhibit myelopoiesis, reduce MDSCrecruitment, and transform existing MDSCs into a lessimmunosuppressive phenotype has shown great potential inpreclinical cancer models. Given the lack of existing strategies totarget MDSCs in infectious diseases, the use of DNMT inhibitorspresents a promising avenue for intervention. While DNMTfrontiersin.orgGjerstorff 10.3389/fimmu.2023.1247715inhibitors have been extensively studied in the context of cancer, theirpotential application in infectious diseases remains unexplored.Further research is needed to investigate the efficacy of DNMTinhibitors in relevant infection models, assessing their ability torestore effective immunity and clear infections. In this context, theymay be used as standalone agents or in combination with antibiotics.Pursuing these novel therapies can lead to significant progress inaddressing the growing threat of untreatable infections.DiscussionUntreatable infections pose a significant threat to individuals andcommunities worldwide with millions of people dying each year andnumbers are increasing. This makes the need for novel therapeuticstrategies more critical than ever. Collectively, the above findings makea strong case for DNMT inhibitors as a powerful tool for relievingMDSC-controlled immune suppression and the use of DNMTinhibitors to target MDSCs in infectious diseases holds great promiseand warrants further investigation. By modulating the immuneresponse and reducing MDSC-mediated immunosuppression,DNMT inhibitors have the potential to become valuable therapeuticFrontiers in Immunology 03tools in the fight against untreatable infections. However, in some typesof infections MDSCs contribute positively to the immune response byfacilitating pathogen clearance and limiting inflammatory damage.Thus, further research is essential to fully understand the precisemechanisms by which MDSCs modulate immune responses invarious types of infections and how this can be modulated withDNMT inhibitors.Author contributionsThe author confirms being the sole contributor of this work andhas approved it for publication.FundingThe study was supported by the Region of Southern Denmark,Pink Tribute, Einar Willumsens foundation, Carl and Ellen Hertzsfoundation, Phycician Sofus Carl Emil Friis and spouse’s foundation,Neye foundation, Agnes and Poul Friis foundation, Emil C. Hertz andspouse’s foundation, Frimodt-Heineke foundation, Olga Doris Friisfoundation, Dagmar Marshalls foundation, the Danish CancerFIGURE 1MDSCs contribute to persistence of infections and can be targeted by DNMT inhibitor treatment. Inflammatory cytokines produced during infectionmobilize and recruit MDSCs to the site of infection. Recruited MDSCs suppress immune effector cells through production of reactive oxygen speciesand immune suppressive proteins. This ultimately suppresses immune responses against pathogens and contributes to unresolved inflammation andchronic infection. DNMT inhibitors have been demonstrated to inhibit the production of MDSCs in the bone marrow and should be considered fortreatment of MDSC-driven infections (the figure was produced using BioRender).frontiersin.orgGjerstorff 10.3389/fimmu.2023.1247715Society, the Novo Nordisk foundation, and the Danish ResearchCouncil for Independent Research.Conflict of interestThe author declares that the research was conducted in theabsence of any commercial or financial relationships that could beconstrued as a potential conflict of interest.Frontiers in Immunology 04Publisher’s noteAll claims expressed in this article are solely those of the authorsand do not necessarily represent those of their affiliatedorganizations, or those of the publisher, the editors and thereviewers. Any product that may be evaluated in this article, orclaim that may be made by its manufacturer, is not guaranteed orendorsed by the publisher.References1. 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Epigenetic targeting of myeloid-derived suppressor cells: time to move into infectious diseases?

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Epigenetic targeting of myeloid-derived suppressor cells: time to move into infectious diseases?

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