The role of Th17 cells in tumor immunity

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Review/Praca poglądowa

The role of Th17 cells in tumor immunity

Znaczenie limfocytów Th17 w odporno ści przeciwnowotworowej

Agnieszka Karczmarczyk *, Marta Karp, Krzysztof Giannopoulos

DepartmentofExperimentalHematooncology,MedicalUniversityofLublin,Lublin,Poland

Introduction

Since 1989 when Mosmann and Coffman showed that murine CD4+ T cells differentiate into two subsets of reciprocal patterns of cytokine secretion and function, deﬁned as CD4+ T helper type 1 (Th1) and Th2, a great progress in understanding of Th cells and certain effector cytokinesutilizedbyThcellshasbeenobserved.Thisclassic divisionwaschangedbythediscoveryofanewCD4+helper T cells population which is characterized by the high expression of IL-17, named CD4+ T helper type 17 (Th17).

More recently, the new Th subsetssuch as Th9 and Th22 cells, which play roles in the modulation of hostimmune responses,werediscovered[1–3].

Th17 cell differentiation

After the discoveryof Th17 cells, manystudies have been focused onthemechanismsthatleadtothe differentiation of CD4+cells.Atleastseveralcytokinesandtheircombina- tions,thepresence ofwhichdetermines theformation and article info

Articlehistory:

Received:28.03.2014 Accepted:03.04.2014 Availableonline:13.04.2014

Keywords:

Th17cells

IL-17

Th17intumorimmunity

Słowakluczowe:

komórkiTh17

IL-17

Th17wodpornościprzeciwnowo- tworowej

abstract

CD4+Thelper(Th)cellsplayanimportantroleinmodulatingimmuneresponses.Th17 cellsarea newlyestablishedThsubpopulation.Th17cellsdifferentiateinthepresence ofTGF-bandIL-6inmiceorIL-1bandIL-6inhumans,dependingonthetranscription factor RORgt. IL-23 stabilizes the Th17 cells phenotype and helps Th17 cells acquire effectorfunctions.Th17secretesIL-17,IL-21,andIL-22,whichplaysigniﬁcantroleinthe immune response against viruses, extracellular bacteria and fungi, as well as in the pathogenesisofinﬂammatorydiseases.ThesystemicandlocalactivityofIL-17andTh17 seemstobeanimportantpartofdevelopmentofautoimmunereaction.Th17cellsubpo- pulation has been described in many types of cancer, including gastric cancer, melanoma, breast cancer, and ovarian cancer, but it remains unclear whether Th17 cells promoteorinhibittumorprogressionandthemechanismoftheirinvolvementintumor immunityisunknown.

This reviewsummarizesthe current knowledge on therole ofTh17 cellsin tumor immunity.

*Correspondingauthorat:DepartmentofExperimentalHematooncology,MedicalUniversityofLublin,ul.Chodźki4a,20-950Lublin, Poland.Tel.:+48817564812;fax:+48817564813.

E-mailaddress:agniecha_p86@o2.pl(A.Karczmarczyk).

ContentslistsavailableatScienceDirect

Acta Haematologica Polonica

journalhomepage:www.elsevier.com/locate/achaem

http://dx.doi.org/10.1016/j.achaem.2014.04.017

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maintenance of Th17 phenotype inanimal modelsand in humans,arealreadyknown.

In mice, transforming growth factor-b (TGF-b) and IL-6 are crucial for Th17 differentiation. Notably naïve T cells stimulatedbyTGF-b only,withoutthe involvementofIL-6, are developinginthe direction of regulatoryT cellsbythe activationof the transcriptionfactorFOXP3.Therefore, IL-6 isanessentialfactorforthedifferentiation ofnaïveTcells into Th17 as it increases the expression of IL-23R and subsequently inhibits the activity of FOXP3. IL-23 is not needed for the early development of mice Th17 cells, but seemsto beinvolved intheexpansion andsurvivalof the Th17cellsubpopulation[4–6].

Inhumans,Th17cells differentiateundersimilarcondi- tions,butwithlittlemorecytokinesinamicroenvironment.

In vitro studies on CD4+ cells taken from the cord blood haveshownthatanoptimumenvironmentforthisprocess requires the presence of IL-1b, IL-6, IL-21, and IL-23. The formation of human Th17 cells in comparison with the murinecellsdependstoagreaterextentonthepresenceof IL-23aswellasthepro-inﬂammatorycytokinessuchasIL- 1bandIL-21[7,8].IL-23isproducedbyactivatedmonocytes, macrophages, dendritic cells and endothelial cells. Binding to its speciﬁc receptor activates JAK/STAT T cell pathway.

IL-23mightbeinvolvedintheupregulationofIL-17produc- tion. It also stabilizes the Th17 cell phenotype and helps Th17cellsacquireeffectorfunctions[8,9].TheroleofTGF-b inthedevelopmentofTh17cellsfromnaïvehumanTcells has been somewhat controversial. What is more, TGF-b appears to determine Th17 cells differentiation ina dose- dependent manner. Lower concentrations of TGF-b in the presenceofIL-6induceTh17differentiation,theproduction of IL-21andthe upregulationof IL-23R,whilehigher doses of this cytokine inhibitIL-23R expression and promotethe Treg phenotype by activation of the transcription factor

FOXP3 [8,10](Fig.1).Inadditionthe lectinreceptorCD161, the humanhomologueof murineNK1.1,hasbeenreported to be expressedin all human Th17 cells in the peripheral blood and inﬂamed tissues. Moreover, in humans the chemokine receptor CCR6 is involved in the process of differentiationofTh17cellphenotype[11,12].

Thedifferentiation of Th17cellsrequires theexpression of the retinoic acid receptor-related orphan receptor-gt (RORgt), which belongs to the retinoic acid-relatednuclear hormone receptor family. Theinduction of RORgt depends on signal transducer and an activator of transcription 3(STAT-3),andtheoverexpressionof RORgtregulatesIL-17 production and Th17 cells differentiation. In human, the overexpressionof RORC2 (thehuman orthologof RORgt)in nativeTcellsinducestheexpressionofIL-17A,IL-17F,IL-26 and CCR6 [7,13].STAT-3 regulatesTh17cell lineagedevel- opment in cooperation with IL-6, IL-21 and IL-23. STAT-3 affectsRORgtexpressionandbindstoIL-17A,IL-17FandIL- 21 promoters [14]. The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor, which can induce Th17 differentiation, presumably through the inhibition of STAT1 and STAT5,which negatively regulatesTh17 development [15, 16]. Recent data have shown that interferon regulatoryfactor4(IRF4)isalsoimportantinthedifferentia- tion of Th17 cells throughthe IL-6 and TGF-b pathway or throughtheIL-21-mediatedpathway[17].

Function of Th17 cells

Th17 cellssecreteanumber ofcytokinesamong whichthe most important is IL-17. IL-17 is the member of the IL-17 family, which consists of six cytokines: IL-17A, IL-17B, IL- 17C, IL-17D, IL-17E and IL-17F. Th17 cells secrete large quantities of IL-17A inhumans,thegene encodingIL-17is localized on chromosome6. IL-17haspleiotropic effecton the tissue cellsand several immunecells. IL-17 stimulates the production of inﬂammatory cytokines, such as IL-6, TNF-a, IL-1b, chemokines (CXCL1, CXCL3, CXCL5, CXCL6), and several growth factors including granulocyte colony- stimulating factor(G-CSF),granulocyte–macrophagecolony- stimulatingfactor(GM-CSF)andvascularendothelialgrowth factor (VEGF) from epithelial cells and ﬁbroblast. This cytokineplaysanimportantroleincombatingextracellular pathogens (bacteria and fungi) by inducing neutrophil maturation and chemotaxis. Furthermore, IL-17 increases theexpression ofintracellularadhesionmolecule1(ICAM1) on epithelial cells and induces the secretion of matrix metalloproteinases(MMPs)thatareinvolvedintissueremo- deling and damage. IL17A signaling occurs through a receptor IL17RA, which is expressed in multipletissues, such ashematopoietic tissue, skin,and lung[18, 19]. Th17 cell also produces other effector molecules, such as IL-21, IL-22,IL-26,IL-6andCCL20.

IL-22belongstoIL-10familyofcytokinesandisproduced by terminally differentiated Th17 cells and activated by Tcells. IL-22hasaprotectiveeffectonepithelialcells. This cytokine stimulates defence, regeneration and healing in tissue through the induction of antimicrobial agents and proteins involved in epithelial cell differentiation and cell Fig.1–DifferentiationandfunctionofTh17cellsinmice

andhuman

Ryc.1–RóżnicowanieifunkcjekomórekTh17umyszyiludzi

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mobility. IL-22 induces antimicrobial proteins (S100 proteins), b-defensins, acute-phase proteins, inﬂammatory cytokinesandchemokinesinkeratinocytes[20,21].

Il-21 is a member of the IL-2 family and mediates its functionsviathe IL-21receptor(IL-21R), whichisexpressed on B cells, T cells and natural killer (NK) cells and non- immune cells such as epithelial cells and ﬁbroblasts. IL-21 stimulatestheproliferationandactivationofCD4+andCD8+

cellsandtheexpansionandactivationofNKcells[22,23].In addition,IL-21regulatesthematurationanddifferentiationof Blymphocytes.Itcanalsopromoteantibodyproductionand antibodyclass switching by theinductionof involved transcriptionfactor(Blip-1,Bcl-6)[24,25].Thiscytokine canalso induce the secretion of chemokines and the production of MMP in non-immune cells, such as epithelial cells and ﬁbroblasts[26].IL-21alsoinducestheexpressionoftheIL-23R [27].

IL-26isamemberoftheIL-10family,whichisproduced bytheactivatedmemoryTcellsandinducestheexpression ofproinﬂammatorycytokines,suchasTNF-aand IL-8,and inhibits cell proliferation [28]. CCL20 is a ligand for CCR6 andit haveanantimicrobial andchemoattractive activities [19].

The role of Th17 in tumor immunity

Th17cell subpopulation hasbeen describedinmanytypes of cancers, including gastric cancer, melanoma, breast cancer,andovariancancer,butitisnotclearwhetherTh17 cellspromoteorinhibittumorprogressionandthemechan- ism of their involvement in tumor immunity isunknown.

Thedevelopment of cancer is affectedby many factors. It depends on the production of proﬁle of pro-inﬂammatory and angiogenic cytokines,antitumor immunity and immu- nogenicityofthetumor[29–31].

Tumor promotion by Th17 cells and IL-17

Potential mechanismsresponsible forthepromotion of tumor growthactivitybyIL-17andTh17cellsinvolveangiogenesis.IL- 17influencesthe proliferationoftumorcells bystimulationof newvessels formationdueto its pro-inflammatory as wellas angiogenic activity. This induces VEGF, which markedly promotes inflammatory and tumor angiogenesis [32]. Moreover, VEGF stimulates the production of TGF-b, which seems to enhancecancergrowthandmetastasisbystimulatingangiogen- esis[33].IL-17alsoinducesIL-6andenhancestheexpressionof ICAM-1infibroblasts.Thesemoleculesplayanimportantrolein angiogenesisandtumorinvasion.IL-6inducesactivationofthe oncogenicsignalSTAT3,resultinginprosurvivalandproangioge- netic genes upregulation [34, 35]. IL-17 seems to induce the productionofIL-8.Itpromotesangiogenicresponseinendothe- lialcells,increasesproliferationandsurvivalofendothelialand tumorcells, and infiltration of neutrophils on the site of the tumor. Expression of IL-8 correlates with angiogenesis and metastasis[35, 36]. IL-17stimulatesthe secretion ofIL-1band TNF-abymacrophages.Thesecytokinesactivateneutrophilsto secrete specific chemokines that recruit them to the site of

inﬂammation. In addition, IL-17 increases the production of angiogenic chemokines such as CXCL1, CXCL5, CXCL6, and CXCL8in endothelialcells andcancer cells.Thesechemokines caninduceproliferationandchemotaxisofvascularendothelial cells, which promote tumor growth [37, 38]. IL-23 may up- regulateIL-17andmatrixmetalloprotease9(MMP-9)tostimulate angiogenesis and reduce the number of CD8+ T cells in the tumor microenvironment. It has also beendemonstrated that tumor cells and tumor-derived ﬁbroblasts secrete monocyte chemotactic protein 1 (MCP-1) mediating the recruitment of Th17 cells [30].Protumor activity mediated by Th17and IL-17 hasbeenobservedbothinmousetumormodelsandinhuman cancerpatients.

Tartour et al. [39] injected nude mice with human cervicaltumorcellstransfectedwithhumancDNAencoding IL-17andfoundthattheygrewmorequicklythanparental tumors.Numasakietal.[38]demonstratedthathumannon- small cell lung cancer transfected with human IL-17 grew faster in severe combined immunodeﬁciency (SCID) mice thandidcontrolnon-smallcelllungcancercells.

In the study of hepatocellular carcinoma significantly higher levels of Th17cells intumorincomparison tonon- tumortissuehavebeendescribed.ThelevelsofTh17cellsare positively correlated with microvesseldensity inthe tumor [40].Alexandrakis et al.[41] inpatients with multiplemye- lomafoundcorrelationbetweenhighlevelsofIL-17inserum and concentration of proangiogenic cytokines, density of bloodvesselsandclinicalstageofthedisease.Inthestudyof gastric cancer the frequency of Th17cells was significantly increasedwhencomparedtohealthydonors.Thepercentage ofTh17cellsinstageIII–IVwashigherthanthatinstageI–II patients [29].Tosoliniandcoworkers [42]reportedthathigh expressionof Th17geneincolorectaltumor wasassociated withpoorprognosis.InthestudybySfanosetal.[43]itwas demonstratedthatTh17cellsinfiltratingthetumorcorrelated inverselywiththeGleasonscoreinprostatecancer.

Wang et al. [44]showed signiﬁcantly higher percentage of Th17 cells in bothcolorectal adenoma (CRA) and color- ectalcarcinoma(CRC)comparedtothatinhealthycontrols.

They observed that the percentage of Th17 cells was decreasedinadvancedstagesofCRAsandCRCsincompar- ison with early stageof the diseases. Also, the concentrations of IL-17A and IL-23 were higher in CRA and CRC patientswhencomparedtothatinhealthycontrols.

Wu etal. [45]reported signiﬁcantly higherfrequency of Th17 cells in untreated acute myeloid leukemia (AML) patients compared to that in healthy controls. They also found increasedconcentrations of IL-6 and TGF-b1in AML patients than in controls; the IL-6 concentrations showed a positive correlation with frequencies of Th17 cells.

Furthermore,thefrequenciesofTh17cellsweresigniﬁcantly reducedinpatientswithcompleteremission(CR)compared to that in the same patients before treatment, and in comparisontonon-CRpatientswhodidnotpresentreduced frequenciesaftertherapy.

In the study of chronic lymphocytic leukemia Jadidi- Niaraghet al. [46] showed lower number of Th17 cells in progressive compared to indolent patients and healthy controls.Additionally,Th17cellsweredecreasedinpatients inII-IVRai stageswhencompared tothatinthoseinearly

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stages0–I.TheyobservedasigniﬁcantdecreaseofTh17cells in unmutated IGHV compared to mutated samples. The mean ﬂuorescence intensity (MFI) of IL-17 was lower in progressiveas comparedto indolentpatients andnormal subjects.EarlierwefoundhigherfrequencyofTh17cellsin patients with CLL, even in patients in early stage of the disease.Wereported thatthe expressionof Th17didnot correlate with disease stage and prognostic factors [54].

Hus et al. [55] observed higher percentages of Th17 cells andIL-17Aplasmalevelsinpatientsinearlyclinicalstages of CLL compared to those in advanced Rai stages and healthycontrols. ThefrequenciesofTh17cellsandIL-17A were lower in patients with adverse prognostic factors.

Furthermore, they found that IL-17A plasma levels were lowerinpatients whorequired therapycompared tothat in patients who were not treated. Biological and clinical effects of Th17 cells and IL-17 in cancer patients are summarizedinTableI.

The anti-tumor function of Th17 cells and IL-17

Theantitumor functionof Th17 cellsreﬂects theinﬂuence ofIL-17onmanycelltypes.IL-17stimulatesthematuration of dendritic cells by increasing the surface expression of MHCclassIImolecules.Thepresentationof tumorantigens to CD8+cells leads to their differentiation in cytotoxic T lymphocytes. IL-17stimulates the production of IL-12 in macrophages,leadingtotheactivationofcytotoxiclympho- cytes.ItisbelievedthatTh17cellsindirectlyaffecttheanti- tumor immunity by recruiting cytotoxic lymphocytes, NK cells,macrophages,neutrophilsanddendriticcells[47,48].

Hirahara et al. [49] have transfected human IL-17 gene into hamsterovariancancercellsandshownasigniﬁcantly lowermetastaticpotential oftumor cellsbydirect modula- tionofinvasivenessandmetastasisaswellasbyincreasing the activity ofNK cells.In amurinemodelMuranski etal.

[50]haveobtainederadicationofadvancedmelanomausing tumor-speciﬁcTh17lymphocytesgeneratedinvitro.

Kryczek et al. [51] have shown a positive correlation betweenthepercentageofTh17tumorinﬁltratingcellsand the percentage of effector CD8+ lymphocytes as well as negative correlation between the percentage of Th17 cells and regulatory T cells in patients with advanced ovarian carcinoma.

Horlock et al. [52] in their study have demonstrated significantlylowernumberofTh17cellsinperipheralblood in HER-positive breast cancer patients when compared to HER-negative patients and healthy controls. Furthermore, thepercentageofregulatoryTcellswassignificantlyhigher inbreastcancerpatientscomparedtohealthyvolunteers.In addition, Jain et al. [53] have reported significantly higher absolute number of blood Th17 cells in patients with chroniclymphocyticleukemiacomparedtohealthycontrols.

They have also demonstrated positive correlation between circulating Th17cells numberand survivalof CLLpatients.

Patients with high Th17 cells number had longer median overallsurvivalthanpatientswithlowTh17cellsnumber.

Insummary, thepresented datasuggest theimportance of Th17 cells in tumor immunity, but their impact on the developmentofcancerremainsundeﬁned.Characterization ofthefunctionalrolesofTh17cells,aswellasidentiﬁcation of the mechanisms underlying Th17 cell heterogeneity in individualtumorsorduringtumordevelopment,isurgently TableI–TheroleofTh17cellsandIL-17intumorimmunity

TabelaI–ZnaczeniekomórekTh17iIL-17wodpornościprzeciwnowotworowej Malignancytype Numberof

patients

Expressionof Th17orIL-17

level

Biological signiﬁcance

Clinical signiﬁcance

References

Hepatocellularcarcinoma 178 " HigherTh17numberscorrelated withhighermicrovesseldensity

HigherTh17numberscorrelated withshorteroverallsurvival

40

Multiplemyeloma 40 " IncreasingserumlevelsofIL-17 positivelycorrelatedwith angiogeneticfactorsuchasTNF, VEGF

IncreasingserumlevelsofIL-17 correlatedwithadvancing diseasestage

41

Acutemyeloidleukemia 42 " IncreasingTGF-b,IL-6,IL-17 concentrationsinplasma,IL-6 andIL-17concentrationsshowed apositivecorrelationwiththe frequenciesofTh17cells

Notassessed 45

Colorectalcancer 231 "Th17gene Notassessed HighexpressionoftheTh17 clustergenescorrelatedwith shorteroverallsurvival

42

Ovariancancer 201 " HigherTh17numberspositively

correlatedwiththepercentage ofeffectorCD8+lymphocytes

HigherlevelsofIL-17correlated withlongeroverallsurvival

55

Chroniclymphocytic leukemia

66 " Notassessed HighercirculatingTh17levels

correlatedwithlongeroverall survival

46

Breastcancer 27 # LowernumberofTh17cells

correlatedwithhigher numbersofTreg

Notassessed 54

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required for the development of effective and speciﬁc antitumorimmunotherapies.

Authors' contributions/Wkład autorów

Accordingtoorder.

Conﬂict of interest/Konﬂikt interesu

Nonedeclared.

Financial support/Finansowanie

Nonedeclared.

Ethics/Etyka

The work described in this article has been carried out in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments invol- ving humans; EU Directive 2010/63/EU for animal experiments; and Uniform Requirements for manuscripts submittedtoBiomedicaljournals.

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