Abstract
Simple SummaryInterleukin-33 (IL-33) is often released from damaged cells, acting as a danger signal. IL-33 exerts its function by interacting with its receptor suppression of tumorigenicity 2 (ST2) that is constitutively expressed on most immune cells. Therefore, IL-33/ST2 signaling can modulate immune responses to participate actively in a variety of pathological conditions, such as cancer. Like a two-faced Janus, which faces opposite directions, IL-33/ST2 signaling may play contradictory roles on its impact on cancer progression through both immune and nonimmune cellular components. Accumulating evidence demonstrates both pro- and anti-tumorigenic properties of IL-33, depending on the complex nature of different tumor immune microenvironments. We summarize and discuss the most recent studies on the contradictory effects of IL-33 on cancer progression and treatment, with a goal to better understanding the various ways for IL-33 as a therapeutic target.Interleukin-33 (IL-33), a member of the IL-1 cytokine family, plays a critical role in maintaining tissue homeostasis as well as pathological conditions, such as allergy, infectious disease, and cancer, by promoting type 1 and 2 immune responses. Through its specific receptor ST2, IL-33 exerts multifaceted functions through the activation of diverse intracellular signaling pathways. ST2 is expressed in different types of immune cells, including Th2 cells, Th1 cells, CD8+ T cells, regulatory T cells (Treg), cytotoxic NK cells, group 2 innate lymphoid cells (ILC2s), and myeloid cells. During cancer initiation and progression, the aberrant regulation of the IL-33/ST2 axis in the tumor microenvironment (TME) extrinsically and intrinsically mediates immune editing via modulation of both innate and adaptive immune cell components. The summarized results in this review suggest that IL-33 exerts dual-functioning, pro- as well as anti-tumorigenic effects depending on the tumor type, expression levels, cellular context, and cytokine milieu. A better understanding of the distinct roles of IL-33 in epithelial, stromal, and immune cell compartments will benefit the development of a targeting strategy for this IL-33/ST2 axis for cancer immunotherapy.
Highlights
Interleukin-33 (IL-33) was identified over a decade ago as an IL-1 cytokine family member [1] and is recognized as a crucial player in innate and adaptive immunity
Son et al revealed upregulation of the genes for proliferation, immune suppression, and cytokine/chemokine receptor in tumor-infiltrating Tregs in comparison to tumor-infiltrating CD4+Foxp3− conventional T cells or splenic Tregs from the same tumor-bearing mouse, confirming IL-33/Suppression of tumorigenicity 2 (ST2) axis as a critical pathway for the preferential accumulation of Tregs in the tumor microenvironment (TME) [116]. These observations provide evidences that Tregs activated by IL-33/ST2 signaling are enriched in TME and exert pro-tumorigenic function in contrast to their counterpart CD4+ T cells
In an aggressive mouse AML model, we demonstrated that recombinant IL-33 (rIL-33) treatment enhanced tumor protective effects by strongly increased expansion of leukemia-reactive CD8+ IFN-γ+ T cells, which resulted in delayed leukemia development and increased overall survival
Summary
Interleukin-33 (IL-33) was identified over a decade ago as an IL-1 cytokine family member [1] and is recognized as a crucial player in innate and adaptive immunity. ST2 was detected exclusively by T helper 2 (Th2) cells [2] but identified later to be expressed on the surface of other activated leukocytes, including Th1 cells, CD8+ T cells, and Natural Killer (NK) cells. IL-33 is one of the alarmins ( called Damage-associated molecular patterns, DAMPs), such as highmobility group box 1 protein (HMGB1), ATP, heat-shock proteins (HSPs), and IL-1α [3,4]. In of the alarmins ( called Damage-associated molecular patterns, DAMPs), 2suofc2h5 as high-mobility group box 1 protein (HMGB1), ATP, heat-shock proteins (HSPs), and IL1α [3,4]. LAonlognwgiwthitthumtuomr or devdeelvoeplompemnet,ntI,LIL-3-333 iiss lilkikeleylydodwonwrengruelgauteldatiendepinitheelpiaitlhceellilsalbucteullpsrebguutlautepdrienguthleatTeMd EindesthpieteTthMeEexidsteisnpgitceontthraediecxtoisryting conrtersaudltisc.toNryevreerstuhletsle.sNs,etvheertinhcerleeasss,edthIeLi-n33creexapseredssIiLo-n33inexstproremssailocnominpsotnroemntas,l scuocmhpaosnCeAntFs,, csruecahtesashiCgAhlFy, scurepaptreessshivigehly supmpirleiesusifvoer tmheiliimeumfuonretrheespiomnmseu, tnheusrecsopnotrnibseu,titnhgutso cthoentturimbuotrinpgrogtoresthsieontuamndomr eptraosgtarseisssmioaninalyndbymreectrausittainsigs immmaiunnlye-by recruiting immune-suppressive tumor-associated macrophages (TAM), myeloid-derived suppressor cells (MDSC), and Tregs.uBpyprceosnsitvraesttu, mthoer-masasjoocriiatyteodfmstaucdroiepshraegveesa(lTtAhMat)s, ymstyeemloiicda-dnedr/iovredloscuapl pprreosdsourctcieolnlso(fMILD-S3C3)e, xaenrdtsTarepg.otBeyntcoinnhtribasitto, ry eNffKetghcrctoeewolmlntsah,tjouDarnmCidtoysm,roagefntrsadotsuwtaedtsoihiesssianbnryoedpvehenmahilleasttn)ahcisaimtntagsmsyibsusotnbetheymaceidconamahpnaptdniov/cenione(rign.letob.s,c.oeatAflhfepcbartodeodtartupeTcrthitvi1uo,ennad(nioe.defr.sIC,LteDa-fn38f3de+cieTntxogcereroltTlsfsh)at1ah,pneaodntpeidlnnentCioaiDntterh8o(i+pib.Teiict.o,cNrreoylKllsee)cfsfeaeolnclfstd, IoDLinnC-n3tsu3a, mtaiennod(rit.he.e, epiethoseilniaolp, hsitlrso)mimaml, uannedcoimmmpounneentcse. T1.hTehdeudaul arlorleoloefoIfLI-L3-333ininrergeguulalatitninggaannttiittuummoorr iimmmmuunnee rreessppoonnsseessdduurirninggtutummororprporgorgersessiosnio.nA. lAonlognwgiwthitthumtuomr or devdeelvoeplompemnet,ntI,LIL-3-333 iiss lilkikeleylydodwonwrengruelgauteldatiendepinitheelpiaitlhceellilsalbucteullpsrebguutlautepdrienguthleatTeMd EindesthpieteTthMeEexidsteisnpgitceontthraediecxtoisryting conrtersaudltisc.toNryevreerstuhletsle.sNs,etvheertinhcerleeasss,edthIeLi-n33creexapseredssIiLo-n33inexstproremssailocnominpsotnroemntas,l scuocmhpaosnCeAntFs,, csruecahtesashiCgAhlFy, scurepaptreessshivigehly supmpirleiesusifvoer tmheiliimeumfuonretrheespiomnmseu, tnheusrecsopnotrnibseu,titnhgutso cthoentturimbuotrinpgrogtoresthsieontuamndomr eptraosgtarseisssmioaninalyndbymreectrausittainsigs immmaiunnlye-by recruiting immune-suppressive tumor-associated macrophages (TAM), myeloid-derived suppressor cells (MDSC), and Tregs.uBpyprceosnsitvraesttu, mthoer-masasjoocriiatyteodfmstaucdroiepshraegveesa(lTtAhMat)s, ymstyeemloiicda-dnedr/iovredloscuapl pprreosdsourctcieolnlso(fMILD-S3C3)e, xaenrdtsTarepg.otBeyntcoinnhtribasitto, ry eNffKetghcrctoeewolmlntsah,tjouDarnmCidtoysm,roagefntrsadotsuwtaedtsoihiesssianbnryoedpvehenmahilleasttn)ahcisaimtntagsmsyibsusotnbetheymaceidconamahpnaptdniov/cenione(rign.letob.s,c.oeatAflhfepcbartodeodtartupeTcrthitvi1uo,ennad(nioe.defr.sIC,LteDa-fn38f3de+cieTntxogcereroltTlsfsh)at1ah,pneaodntpeidlnnentCioaiDntterh8o(i+pib.Teiict.o,cNrreoylKllsee)cfsfeaeolnclfstd, IoDLinnC-n3tsu3a, mtaiennod(rit.he.e, epiethoseilniaolp, hsitlrso)mimaml, uannedcoimmmpounneentcse. lAl cboemttepraurntmdeernsttainndiTnMg oEf tihsebpelceoiomtrionpgicinroclreesaosifnIgLl-y33iminpthoerteapnitthienliadle, vsterloompianl,ganmdore effeimctmivuenaepcperlol accohmepsairntmcaenncteirniTmMmEuinsobtehceormapinegutiniccsr.easingly important in developing more effective approaches in cancer immunotherapeutics
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