Magdalena Plebanski

Xin Chen

Frontiers in Immunology

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Frontiers in ImmunologyOPEN ACCESSEDITED AND REVIEWED BYStephen Robert Daley,Queensland University of Technology,Australia*CORRESPONDENCEXin Chenxchen@um.edu.moMagdalena Plebanskimagdalena.plebanski@rmit.edu.auRECEIVED 22 May 2023ACCEPTED 18 July 2023PUBLISHED 01 August 2023CITATIONChen X and Plebanski M (2023) Editorial:The role of TNF-TNFR2 signal inimmunosuppressive cells and itstherapeutic implications, volume II.Front. Immunol. 14:1227003.doi: 10.3389/fimmu.2023.1227003COPYRIGHT© 2023 Chen and Plebanski. This is anopen-access article distributed under theterms of the Creative Commons AttributionLicense (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 EditorialPUBLISHED 01 August 2023DOI 10.3389/fimmu.2023.1227003Editorial: The role of TNF-TNFR2signal in immunosuppressivecells and its therapeuticimplications, volume IIXin Chen1* and Magdalena Plebanski2*1State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences,University of Macau, Macau, Macau SAR, China, 2School of Health and Biomedical Sciences, RMITUniversity, Bundoora, VIC, AustraliaKEYWORDSTNF, TNFR2, CD4+Foxp3+regulatory T cells, inflammation, cancer, autoimmune diseasesEditorial on the Research TopicThe role of TNF-TNFR2 signal in immunosuppressive cells and itstherapeutic implications, volume IIIntroductionThere is compelling evidence that TNFR2 signaling plays a decisive role in theactivation, expansion, function and phenotypical stability of CD4+Foxp3+ regulatory Tcells (Tregs) (1–4). Current research focuses on the translation of this property of TNFR2into novel treatment for major human diseases, while the molecular basis underlying Treg-stimulatory effect of TNFR2 is also actively pursued. This Research Topic showcases thelatest experimental studies as well as expert perspectives incorporating recent findings inthe literature.Inhibition of TNFR2 signaling forcancer immunotherapyChen, Y. et al. from Adlai Nortye USA Inc. reported that a humanized antagonisticantibody, AN3025, at sub-nanomolar affinity binds to the extracellular domain of humanTNFR2. In vitro treatment with AN3025 inhibited the immunosuppressive effect of humanTregs (hTregs), resulting in an enhanced proliferation and IFNg production by co-culturedeffector T cells (Teffs). In TNFR2 humanized mice, AN3025 treatment markedly inhibitedthe growth of MC38 tumor, accompanied by the reduction of tumor-infiltrating Tregs andan increase in the number of effector CD4 and CD8 T cells in the tumor. Further, the invivo anti-tumor effect of AN3025 could be enhanced when used together with anti-PD-L1antibody. Thus, this antagonistic anti-TNFR2 antibody may be used as a monotherapy orcombined with other immune therapeutics in the treatment of cancer (Chen, Y. et al.)frontiersin.org01Chen and Plebanski 10.3389/fimmu.2023.1227003Levels of soluble TNFR2 inthe circulation as a cancerdiagnostic biomarkerBased on the previously published data, Kartikasari et al. fromRMIT University analyzed the correlation of levels of solubleTNFR2 (sTNFR2) in the blood and the risk of cancer. The resultsshow that the levels of sTNFR2 were markedly enhanced incirculation of patients with spectrum of cancers, includingcolorectal cancer, ovarian cancer, breast cancer, non-Hodgkin’slymphoma, Hodgkin’s lymphoma, lung cancer, hepatocarcinoma,and glioblastoma. A random-effect meta-analysis shows that thecancer-specific odds ratio (OR) significantly correlated between theelevated levels of circulating sTNFR2 and the risk of colorectalcancer, non-Hodgkin’s lymphoma, and hepatocarcinoma.Consistent with the notion that TNFR2 promotes thedevelopment of cancer, this study for the first time provides clearevidence that sTNFR2 in the circulation may be used as a diagnosticbiomarker for certain types of cancers (Kartikasari et al.).Activation of TNFR2 signaling for thetreatment of inflammatory diseasesPreviously, it was shown that the clinical effect of anti-TNFantibody (adalimumab) on rheumatoid arthritis is at least partiallymediated by the elevated levels of transmembrane bound TNFexpression on monocytes and the expansion of Tregs throughTNFR2 signaling (5). This may represent a common mechanismof some anti-inflammatory or immunosuppressive therapeutics.Since tetrandrine (TET), a small molecular compound isolatedfrom Chinese herb medicine, was found to have similar effect asadalimumab (6). Chen, S. et al. from University of Macau exploredthe possibility of transforming their study on TET into a treatmentfor psoriasis. To this end, TET nanoemulsion was topicallyadministered on a mouse model of psoriasis, and this treatmentresulted in the expansion of TNFR2-expressing Tregs andinhibition of skin inflammation in WT or TNFR1 KO mice, butnot in TNFR2 KO mice (Chen, S. et al.).Lambuk et al. from Universiti Sains Malaysia systemicallyanalyzed the literature regarding the role of TNF, TNFR1 andTNFR2 in glaucomatous neurodegeneration. They concluded thatselectively targeting certain TNF receptors may represent a moreeffective and safer strategy in the treatment of glaucoma, ascompared with the global blockage of TNF, given TNFR2activation of Tregs can exhibit a potent immunosuppressive effect(Lambuk et al.).Vargas et al. from University Hospital Würzburg developed anew TNFR2 agonist, designated NewSTAR2, which was a single-chain encoded murine TNF80 trimer fused to the C-terminus of anirrelevant IgG1 molecule carrying the N297A mutation to avoid/minimize interaction with Fcg-receptors (FcgRs) and improveserum retention. Single dose injection of NewSTAR2 resulted in a>3-fold increase of Tregs after 5 days of treatment. Tregs inNewSTAR2-treated mice exhibited enhanced suppressive activity,Frontiers in Immunology 02and upregulation of Treg markers such as CD39. Pretreatment withNewSTAR2 could protect mice from allogeneic hematopoietic celltransplantation-induced acute GvHD (Vargas et al.).To date, the exact role of TNFR2 signaling in the outcome oftransplantation of solid organ or islet cells remains elusive.Kouyoumdjian et al. from McGill University thoroughly analyzedthe published data and concluded that TNFR2 signaling is beneficialin kidney and islet transplantation. Nevertheless, the roles ofTNFR2 signaling and its potential therapeutic value in other typesof solid organ transplantation should be further clarified by futurestudies (Kouyoumdjian et al.).Skartsis et al. from University of California San Franciscoexplored the effects of pro-inflammatory factors on hTregs. Theyfound that the treatment with IL-6 and TNF enhanced proliferationof Tregs in a TNFR2-dependent manner, without causing lineagedestabilization. The results prompted the authors to develop aprotocol using TNF, IL-6 and CD28 super-agonist to expand thefunctional Tregs ex-vivo for adoptive Treg transfer therapy(Skartsis et al.).Differential responses of Tregs andTeffs to TNFR2 co-stimulation attranscriptomic and metabolic levelsTNFR2 can be expressed by the activated T effector cells (7).Mensink et al. from Leiden University showed differential responsesof human Tconvs (CD4+ conventional T cells) and tTreg (thymusderived Tregs) to TNFR2 co-stimulation at the transcriptomic andmetabolic levels. Their results showed that both activated humanTconvs and tTregs could respond to TNFR2 stimulation, but in adifferent fashion, with the breadth of the transcriptomic changesmuch larger in tTregs. This suggests a greater impact of TNFR2 co-stimulation on the transcriptome of tTregs versus that of Tconvs.TNFR2 could also play a role in the metabolism of both tTregs andTconvs. Its signal could remodel glutamine metabolism in both celltypes. However, TNFR2 only enhanced glycolysis and TCA cycle intTreg (Mensink et al.).Taken together, the 9 publications in this Research Topicinclude translational research, mechanistic studies, meta-analysisand literature analysis. They showcase major directions and aim tohelp the research community to understand current progress in thisrapidly growing field. Currently, a number of TNFR2-targetingantibodies are under clinical investigation, including those withboth antagonistic or agonistic properties. The publications in thisResearch Topic also help set up the context to understand theclinical trial results which are expected to become available in thenear future.Author contributionsAll authors listed have made a substantial, direct andintellectual contribution to the work, and approved itfor publication.frontiersin.orgChen and Plebanski 10.3389/fimmu.2023.1227003FundingThis work was supported by University of Macau under GrantsMYRG2022-00260-ICMS, SKL-QRCM-IRG2023-022 andCPG2023-00025-ICMS, and funded by The Science andTechnology Development Fund, Macao SAR (FDCT) under grant0099/2021/A2, and 0007/2022/AKP. MP is an NHMRC SeniorResearch Fellow.AcknowledgmentsThe authors thank Ms. Zhaoxiong Wang for her help in thepreparation of this editorial.Frontiers in Immunology 03Conflict of interestThe authors declare that the research was conducted in theabsence of any commercial or financial relationships that could beconstrued as a potential conflict of interest.Publisher’s noteAll claims expressed in this article are solely those of the authorsand do not necessarily represent those of their affiliated organizations,or those of the publisher, the editors and the reviewers. Any productthat may be evaluated in this article, or claim that may be made by itsmanufacturer, is not guaranteed or endorsed by the publisher.References1. Chen X, Bäumel M, Männel DN, Zack Howard OM, Oppenheim JJ. Interactionof TNF with TNF receptor type 2 promotes expansion and function of mouse CD4+CD25+ T regulatory cells. J Immunol (2007) 179(1):154–61. doi: 10.4049/jimmunol.179.1.1542. Chen X, Subleski JJ, Kopf H, Zack Howard OM, Männel DN, Oppenheim JJ.Cutting edge: expression of TNFR2 defines a maximally suppressive subset of mouseCD4+CD25+FoxP3+ T regulatory cells: applicability to tumor-infiltrating T regulatorycells. J Immunol (2008) 180(10):6467–71. doi: 10.4049/jimmunol.180.10.64673. Chen X, Oppenheim JJ. TNF-alpha: an activator of CD4+FoxP3+TNFR2+regulatory T cells. Curr Dir Autoimmun (2010) 11:119–34. doi: 10.1159/0002892014. Chen X, Wu X, Chen X, Zhou Q, Zack Howard OM, Netea MG, Oppenheim JJ.TNFR2 is critical for the stabilization of the CD4+Foxp3+ regulatory T. cell phenotypein the inflammatory environment. J Immunol (2013) 190(3):1076–84. doi: 10.4049/jimmunol.12026595. Chen X, Oppenheim JJ. Therapy: Paradoxical effects of targeting TNF signallingin the treatment of autoimmunity. Nat Rev Rheumatol (2016) 12(11):625–6. doi:10.1038/nrrheum.2016.1456. He T, Yang D, Li XQ, Jiang M, Islam MS, Chen S, et al. Inhibition of two-porechannels in antigen-presenting cells promotes the expansion of TNFR2-expressingCD4(+)Foxp3(+) regulatory T cells. Sci Adv (2020) 6(40). doi: 10.1126/sciadv.aba65847. Chen X, Hamano R, Subleski JJ, Hurwitz AA, Zack Howard OM, Oppenheim JJ.Expression of costimulatory TNFR2 induces resistance of CD4+FoxP3- conventional Tcells to suppression by CD4+FoxP3+ regulatory T cells. J Immunol (2010) 185(1):174–82. doi: 10.4049/jimmunol.0903548frontiersin.org

Editorial: The role of TNF-TNFR2 signal in immunosuppressive cells and its therapeutic implications, volume II

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Editorial: The role of TNF-TNFR2 signal in immunosuppressive cells and its therapeutic implications, volume II

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