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SensitizingAgentsforCancerResistant toCellMediatedImmunotherapy
IMMUNOTHERAPYINRESISTANT CANCER:FROMTHELABBENCHWORK
TOITSCLINICALPERSPECTIVES VOLUME2
SensitizingAgentsforCancerResistanttoCell MediatedImmunotherapySeries
SeriesEditor:BenjaminBonavida,PhD
Volume1:AutophagyinImmuneResponse:ImpactonCancerImmunotherapy
EditedbySalemChouaib
Volume2:ImmunotherapyinResistantCancer:FromtheLabBenchWorktoItsClinicalPerspectives
EditedbyJorgeMorales-MontorandMarianaSegovia-Mendoza
UpcomingVolumes:
ImmunotherapeuticStrategiesfortheTreatmentofGlioma
EditedbyMichaelLimandChristopherJackson
BreakingTolerancetoUnresponsivenesstoImmunotherapybyNaturalKillerCells
EditedbySandroMatosevic
NKcellsincancerimmunotherapy:SuccessesandChallenges
EditedbyAnahidJewett
BreakingTolerancetoPancreaticCancerUnresponsivetoImmunotherapy
EditedbyKasuyaHidekiandItzelBustosVillalobos
IMMUNOTHERAPYIN
RESISTANTCANCER:FROM THELABBENCHWORKTO ITSCLINICALPERSPECTIVES
VOLUME2
Editedby
JORGE MORALES-MONTOR
DepartamentodeInmunologı´a,InstitutodeInvestigacionesBiomedicas, UniversidadNacionalAuto ´ nomadeMexico,MexicoCity,Mexico
MARIANA SEGOVIA-MENDOZA
DepartamentodeFarmacologı´a,FacultaddeMedicina, UniversidadNacionalAuto ´ nomadeMe ´ xico,MexicoCity,Mexico
AcademicPressisanimprintofElsevier 125LondonWall,LondonEC2Y5AS,UnitedKingdom 525BStreet,Suite1650,SanDiego,CA92101,UnitedStates 50HampshireStreet,5thFloor,Cambridge,MA02139,UnitedStates TheBoulevard,LangfordLane,Kidlington,OxfordOX51GB,UnitedKingdom ©2021ElsevierInc.Allrightsreserved.
Nopartofthispublicationmaybereproducedortransmittedinanyformorbyanymeans,electronicor mechanical,includingphotocopying,recording,oranyinformationstorageandretrievalsystem,without permissioninwritingfromthepublisher.Detailsonhowtoseekpermission,furtherinformationaboutthe Publisher’spermissionspoliciesandourarrangementswithorganizationssuchastheCopyrightClearance CenterandtheCopyrightLicensingAgency,canbefoundatourwebsite: www.elsevier.com/permissions.
ThisbookandtheindividualcontributionscontainedinitareprotectedundercopyrightbythePublisher(other thanasmaybenotedherein).
Notices
Knowledgeandbestpracticeinthisfieldareconstantlychanging.Asnewresearchandexperiencebroadenour understanding,changesinresearchmethods,professionalpractices,ormedicaltreatmentmaybecome necessary.
Practitionersandresearchersmustalwaysrelyontheirownexperienceandknowledgeinevaluatingandusing anyinformation,methods,compounds,orexperimentsdescribedherein.Inusingsuchinformationormethods theyshouldbemindfuloftheirownsafetyandthesafetyofothers,includingpartiesforwhomtheyhavea professionalresponsibility.
Tothefullestextentofthelaw,neitherthePublishernortheauthors,contributors,oreditors,assumeanyliability foranyinjuryand/ordamagetopersonsorpropertyasamatterofproductsliability,negligenceorotherwise,or fromanyuseoroperationofanymethods,products,instructions,orideascontainedinthematerialherein.
LibraryofCongressCataloging-in-PublicationData
AcatalogrecordforthisbookisavailablefromtheLibraryofCongress
BritishLibraryCataloguing-in-PublicationData
AcataloguerecordforthisbookisavailablefromtheBritishLibrary
ISBN:978-0-12-822028-3
ForinformationonallAcademicPresspublications visitourwebsiteat https://www.elsevier.com/books-and-journals
Publisher: StacyMasucci
AcquisitionsEditor: RafaelTeixeira
EditorialProjectManager:SamanthaAllard
ProductionProjectManager: PunithavathyGovindaradjane
CoverDesigner: GregHarris
TypesetbySPiGlobal,India
CoverFigureInsert
Thecoverfigureshowshowatumorcell (graycircle)isbeingrecognizedbydifferent immunecells,solublefactors,andantibodies.Thisrecognitionisstrengthenedafter pharmacologicalorbiologicaltherapies (whitemolecules).
TheeditorswouldliketothankLic.Rosa FloresHerna ´ ndezandMtro.AndiEspinoza Sa ´ nchez,FacultaddeMedicina,Universidad NacionalAuto ´ nomadeMexico(UNAM),for therealizationofthecoverimage.
AimsandScopeforSeries“Sensitizing AgentsforCancerResistanttoCell MediatedImmunotherapy”
Theroleoftheimmunesystemintheeradicationofcancershasbeeninvestigatedfor severaldecadeswithcontroversialfindings. Thecontroversywastheresultofapoorunderstandingoftheunderlyingmechanisms thatgovernresponsivenessandunresponsiveness.Hence,significantadvanceshave beenmadewithrespecttotheregulationof thehostimmuneresponseagainstcancer andseveralimmunotherapeuticshavebeen recentlyintroducedandusedclinically.These includebothantibodyandcell-mediated immunitytargetingthecancercells.Suchimmunotherapiesledtosignificantclinical responsesinvariouscancertypesthatwere unresponsivetoconventionaltherapies. However,onlyasubsetofcancerpatients respondstosuchimmunotherapeuticsand alsothereisarespondingsubsetthatdevelops resistancetofurthertreatment.Variousstudieshaveexaminedpotentialunderlying mechanismsinvolvedinresistanceandidentifiedavarietyofgeneproductsthatplaypivotalrolesinmaintainingtheresistant phenotypeofthecancercellstocell-mediated immunotherapy.
Themainobjectiveoftheproposedseries “SensitizingAgentsforCancerResistanceto CellMediatedImmunotherapy”isthedevelopmentofindividualvolumesthatarefocusedontheapplicationofparticular
sensitizingagentsthat,whenusedincombinationwithcell-mediatedimmunotherapy, resultinthereversalofresistance.
Avarietyofdifferentclassesofimmunosensitizingagentshasbeenreported.Eachindividualvolumewillfocusononeclassof immunosensitizingagentsandtheireffects onthereversalofcell-mediatedimmuneresistanceindifferentcancers.Emphasiswillbeon biochemical,molecular,andgeneticmechanismsbywhichthesensitizingagentsmediate theireffectsindividuallyand/orincombinationwithimmunotherapy.Eacheditorwill compilenon-overlappingreviewchapterson thetherapeuticroleofspecificsensitizing agentsusedincombinationwithconventional immunotherapyandthereversalofresistance.Therewillalsobeanemphasison discriminationofresponsesobtainedinvariouscancertypes.
Thescopeoftheseriesistoprovide updatedinformationtoscientistsandcliniciansthatisvaluableintheirquesttogather information,carryoutnewinvestigations, anddevelopnovelimmunosensitizing agentsthatarebothmorepotentandalso thatmightbeactivewherebytheexisting oneswerenotactive.
Dr.BenjaminBonavidaPhD (SeriesEditor)
AbouttheSeriesEditor
Dr.BenjaminBonavida,PhD(Series Editor),iscurrentlydistinguishedresearch professorattheUniversityofCalifornia,Los Angeles(UCLA).Heisaffiliatedwiththe DepartmentofMicrobiology,Immunology andMolecularGenetics,UCLADavidGeffen SchoolofMedicine.Hisresearchcareer,thus far,hasfocusedoninvestigationsinthe fieldsofbasicimmunochemistryandcancer immunobiology.Hisresearchinvestigations haverangedfromthebiochemical,molecular, andgeneticmechanismsofcell-mediated killingandtumorcellresistancetochemoimmunocytotoxicdrugs.Thereversaloftumorcellresistancewasinvestigatedbythe useofvariousselectedsensitizingagents basedonmolecularmechanismsofresistance. Intheseinvestigations,therewasthenewly characterizeddysregulatedNF-κB/Snail/
YY1/RKIP/PTENloopinmanycancersthat wasreportedtoregulatecellsurvival,proliferation,invasion,metastasis,andresistance. Emphasiswasfocusedontherolesofthe tumorsuppressorRafkinaseinhibitorprotein (RKIP)andthetumorpromoterYinYang1 (YY1)andtheroleofnitricoxideasachemoimmuno-sensitizingfactor.Manyoftheaforementionedstudiesarecenteredontheclinical challengingfeaturesofcancerpatients’failure torespondtobothconventionalandtargeted therapies.Theeditorhasbeenactiveinthe organizationofregularsequentialinternationalminiconferencesthatarehighlyfocused ontherolesofYY1,RKIP,andnitricoxide incancerandtheirpotentialtherapeutic applications.
Severalbookseditedorcoeditedbythe editorhavebeenpublished.Inaddition, theeditorhasbeentheserieseditorofbooks (over23)publishedbySpringeron Resistance toAnti-CancerTargetedTherapeutics.Inaddition,theeditorispresentlytheserieseditor ofthreeseriespublishedbyElsevier/ AcademicPresson CancerSensitizingAgents forChemotherapy,SensitizingAgentsforCancer ResisttoCellMediatedImmunotherapy,and BreakingTolerancetoAnti-CancerImmunotherapy.Lastlytheeditoristheeditorinchiefof theJournal CriticalReviewsinOncogenesis Theeditorhaspublishedover500research publicationsandreviewsinvariousscientific journalsofhighimpact.
Acknowledgments: TheEditorwishesto acknowledgetheexcellenteditorialassistanceofMs.InesaNavasardyan,whohas workeddiligentlyinthecompletionofthis volume,namely,inboththeeditingand formattingofthevariouscontributionsof thisvolume.
TheEditoracknowledgestheDepartment ofMicrobiology,Immunology,andMolecularGeneticsandtheUCLADavidGeffen
SchoolofMedicinefortheircontinuous support.TheEditoralsoacknowledgesthe assistanceofMr.RafaelTeixeira,AcquisitionsEditorforElsevier/AcademicPress, andtheexcellentassistanceofMs.Samantha Allard,EditorialProjectManagerfor Elsevier/AcademicPress,fortheircontinuouscooperationthroughoutthedevelopmentofthisbook.
AimsandScopeoftheVolume
Weeditedabook,thatisdedicatedtothe assemblyofthelatestinformationof anticancer-mediatedimmunotherapyandbiologicalfactorsassociatedwithtumormicroenvironment,tobreakpossibleresistanceto immunotherapies.Theroleoftheimmune systemintheeradicationofcancershas beeninvestigatedforseveraldecadeswith controversialfindings.Thecontroversywas theresultofapoorunderstandingoftheunderlyingmechanismsthatgovernresponsivenessandunresponsiveness.Hence,significant advanceshavebeenmadewithrespectto theregulationofthehostimmuneresponse againstcancerandseveralimmunotherapeuticshavebeenrecentlyintroducedandused clinically.Theseincludebothantibodyand cell-mediatedimmunitytargetingthecancer cells.Suchimmunotherapiesledtosignificant clinicalresponsesinvariouscancertypes thatwereunresponsivetoconventional therapies.However,onlyasubsetofcancer patientsrespondstosuchimmunotherapeuticsandalsothereisarespondingsubset thatdevelopsresistancetofurthertreatment. Variousstudieshaveexaminedthepotentialunderlyingmechanismsinvolvedin
resistanceandidentifiedavarietyofgeneproductsthatplaypivotalrolesinmaintainingthe resistantphenotypeofthecancercellstocellmediatedimmunotherapy.Avarietyof differentclassesofimmunosensitizingagents hasbeenreported.Ourbookfocuseson immunosensitizingagentsandtheireffects onthereversalofcell-mediatedimmuneresistanceindifferentcancers.Emphasiswasput onthebiochemical,molecular,andgenetic mechanismsbywhichthesensitizingagents mediatetheireffectsindividuallyand/or incombinationwithimmunotherapy.The chaptersinthisbookarerelatedtothetherapeuticroleofspecificsensitizingagents usedincombinationwithconventionalimmunotherapyandthereversalofresistance. Thereisalsoanemphasisondiscrimination ofresponsesobtainedinvariouscancer types.Thescopeofthebookistoprovide updatedinformationtoscientistsand cliniciansthatisvaluableintheirquestto gatherinformation,carryoutnewinvestigations,anddevelopnovelimmunosensitizing agentsthatarebothmorepotentandalso mightbeactivewherebytheexistingones werenotactive.
AbouttheVolumeEditors
Dr.JorgeMorales-Montor studiedbiology attheIztacalaUNAMFacultyofHigherStudies,obtainingthetitlein1992.Heobtaineda doctor’sdegreeinOctober1997.Hisdoctoral thesiswasrecognizedwiththeLolaandIgo Flisser-PUISAwardtothebestgraduatethesis atthenationallevelintheareaofparasitology,a recognitionthathehasalsolaterreceivedasa tutor,sinceoneofhisdoctoratestudentswon thesameawardin2008.InNovember1997, hebeganapostdoctoralstayattheDepartment ofCellularBiologyattheUniversityofGeorgia, inthelaboratoryofDr.RaymondT.Damia ´ n, oneofthemostrecognizedparasitologistsin theworld.Dr.Moralesreceivedagrantfrom theFogartyFoundation(oneofthemostprestigiousinIbero-America)tocarryoutresearch onschistosomiasisinthemandrel,beingaPanAmericanFellowfor4years.Dr.RayDamia ´ n wouldwriteyearslater,whichassuredthat withoutadoubt,JorgeMorales-Montorhad beenthebestpostdoctoralresearcherwith whomhecollaboratedinhisnearly35-yearcareer.HewasrepatriatedtoMexicoin2001by
CONACYTandjoinedtheDepartmentof ImmunologyoftheInstituteofBiomedical ResearchofUNAMasAssociateInvestigator “C”.Injust9years,hemanagedtoclimbthe entireladderofuniversityacademicpositions, tobecomeaDefinitiveCTitularResearcherat theInstituteofBiomedicalResearch.Thesame isreflectedintheLevelofPremiumsforAcademicPerformance,whereithasreachedthe highestlevelcurrently:LevelD,forthethird consecutiveperiod.AlsointheNational SystemofResearchers,hehashadthesame growth,startingin1997asacandidate, and,todate,beingpromotedtoLevelIII,the highest,forthethirdconsecutiveperiod. Dr.Morales-Montorhasbeeninvitedtoparticipateindifferentcongresses(morethan 100).Inaddition,heispartoftheeditorial committeeofmorethan15indexedinternationaljournals.Someofhismostimportant contributionsarepartiallydeterminingthe roleofsteroidhormonesinimmunological sexualdimorphism,inthepolarizationof theimmuneresponse,andintheantigenic presentation.Hehasalsomadeveryrelevant studiesinrelationtohowdifferentphysiologicalstages,howtheestrouscycle,age, sex,orpregnancyaffectthefunctioningof theimmune,endocrinological,andnervous system,andwhatmoleculescouldbethedeterminantsinthiscontextofnet.Ithasbeen shownthatthecentralnervoussystemisinvolvedintheregulationoftheimmuneresponsetoparasiticinfections,andtheeffect ofthisactivationonvariousbehaviorsof theinfectedhost.Butthecentralnervoussystemhasprovidedinterestingdataaboutits impactintheparasitologyapproach.For
instance,amodernconceptisdepictedby howthecentralnervoussystemmodulates thegeneandproteomicregulationofthedifferentsexsteroidsinparasites,whichareinvolvedinimportantfunctionsofparasites suchasestablishment,growth,andreproduction.Finally,thepracticaluseofthe knowledgeacquiredbytheearliermentionedstudieshasbeenappliedtoatheory thathecallsolddrugs,newuses:theuseof hormonesandantihormonesasantiparasitic therapy.Hehasalsoenteredthestudyofenvironmentalcontamination,specificallyendocrinedisruptorsanddisease,studying theirroleintwoveryimportantdiseasesin thecountry:cancerandobesity,projects withwhichhehasformedtwoconsortiums ofinvestigation.ItsresultsareaveryimportantcontributiontothehealthofbothMexicansandLatinAmericansingeneral,since thisiswhereserioushealthproblemsrelated toparasiticinfections,cancer,andobesity areconcentrated.Hisinvestigationsarecharacterizedbyanexhaustiveandmeticulous experimentalwork,andhisscientificproductionalreadyhas153articlesininternationalindexedjournals,andthemajorityas thefirstauthororcorrespondingauthor. Hehasmorethan3000citationstohisworks, andanh-indexof25,oneofthehighestin thecountry’sscientificcommunity.Hisarticlespublishedinhigh-impactinternational journalsincludeNature,PlosOne,Journal ofImmunology,JournalofInfectiousDiseases,JournalofInterferonandCytokineResearch,andamongothers.Infact,recently, his2015article,TheRoleofCytokinesin BreastCancerDevelopmentandProgression,publishedintheJournalofInterferon andCytokineResearch,wasthesubjectofa pressreleasereleasedbyMaryAnnLiebert Publications.Thisissentallovertheworld, tonewspapers,Journals,scientists,radio, TV,popularmagazines,towhatisconsideredasaveryimportantcontributionina
certainareaofscience.Veryfewscientificarticlesarereleasedas“pressrelease.”Heis alsothe4thmostcitedauthorintheareaof parasitologyinthecountry.Hehasalso editedseveralbooksandpublishedmore than55chaptersinbooks,nationalandforeign.Inthisarea,recently,thechapter“The RoleofSexSteroidsintheHost-ParasiteInteraction,”publishedintheinternational book“SexSteroids”in2012,reachedthefigureof28,000downloads,whichmeans thedegreeofattentionthathasafterreceivinghiswork;theforegoingmakesitclear thatDr.Morales-Montor’sworkishighly relevantandwidespreadamongthenational andinternationalacademiccommunity,and hisbrilliantcareerhasearnedhimmorethan 30awards,suchastheMiguelAlema ´ n ValdezAwardintheareaofHealth2006, theDistinctionNationalUniversityfor YoungAcademicsintheareaofResearch inNaturalSciences2006,theCANIFARMA VeterinaryPrize2007and2009inthearea ofBasicResearch,andthe2009Heberto CastilloMartı´nezCapitalCityAwardfor YoungLatinAmericanAcademicsinResearchBasic,andforthethirdconsecutive congress,in2011,oneofhisworkswas awardedthe“Dr.Jos eEleuterioGonza ´ lez” Award,forthebestworkofandresearchat theXXVINationalCongressofResearchin Medicine,tonamejustafewofitsachievements.Hehasalsobeenawardedmanydistinctions,suchasjoiningtheMexican AcademyofSciences(2005),andbeingone ofthefewMexicanscientiststobeinducted totheLatinAmerican AcademyofSciences (2008),TheNationalAcademyofMedicine, theNewYorkAcademyofSciences,the AmericanAssociationofImmunologists aredeservedrecognitionsforhisacademic qualityandcareer.Hehasgraduatedanddirectsmorethan35bachelor’s,8master’s,and 15doctoratestudents;hasdirectedmore than30socialservicestudents;andon
researchstaysinhislaboratory.Hisacademicleadershipisreflectedinthetrust andrespectthathispeersconferonhim, havingbeenPresidentoftheMexicanSocietyofParasitology(oneoftheoldest andmostprestigiousscientificsocietiesin thecountry)andcurrentlybeingPresident, andfoundingmember,oftheMexicanSocietyofNeuroimmunoendocrinology,since 2011.Duetoitsscientificcuriosity,itisin theprocessoffoundingtheMexicanSociety forTranslationalEnvironmentalBiomedicine.Hehasbeeninvitedtoeditspecialvolumesinvariousmagazineswith internationalcirculationandisamember oftheeditorialcommitteeofmagazinesof importanceinhisareaofwork,suchasParasiteImmunology,TheOpenParasitologyJournal,andamongothers.Hehasbeenajuryfor theArturoRosenbluethAwardsforthebest CINVESTAVDoctoralThesis,ajuryforthe LolaandIgoFlisser-PUIS2010Awards,and
ajuryfortheHebertoCastilloAward,forthe bestLatinAmericanResearcher2012, awardedbytheFederalDistrictGovernment. Itisnoteworthythatheisanoutstandingscientist,whohascontributedtothescientificresearchofMexicowiththegenerationofnew frontierknowledgeintheworldandwith thetrainingofhigh-levelhumanresources.
Affiliationsandexpertise
HeadofLaboratoryofNeuroinmunoendocrinology,DepartmentofImmunology, InstituteofBiomedicalResearch,National AutonomousUniversityofMexico(UNAM), hisexpertiseisintranslationalbiomedicine, tumormicroenvironment,immunology, breastandcolorectalcancer,andinfectious diseases.Allofthemrelatedtoenvironment andtheneuroimmunoendocrinenetwork.
Dr.MarianaSegovia-Mendoza studied theBachelorofBiologicalPharmaceutical ChemistryattheUniversidadNacional Auto ´ nomaMetropolitana-Xochimilcoin MexicoCityobtainingthetitlein2011.Later, shestudiedamaster’sdegreeattheNational InstituteofCancerologyinMexicoCity.Inthis period,shedelvedintothestudyofdifferent endocrinetherapiesandtreatmentsusedin cervicalcancer.InJuly2012,shecarriedout herdoctoralstudiesatthe“SalvadorZubira ´ n” NationalInstituteofNutritioninMexico City,whereshespecializedinbreastcancer, hormones,andtargetedtherapyagainst thisdisease.Duringherdoctoralstudies, shedidaresearchstayintheDepartmentof
BiochemistryandMolecularBiologywith Dr.MauricioReginatooftheDrexelUniversityCollegeofMedicineinthecityofPhil1adelphia,UnitedStates,whichledtoan internationalcollaboration.Attheendof herdoctoralstudies,shereceivedapostdoctoralgrantfromtheNationalInstituteof Nutrition“SalvadorZubira ´ n”whichlasted oneyear.ShealsocompletedasecondpostdoctoralstayintheDepartmentofNeuroimmunoendocrinologyoftheInstituteof BiomedicalResearchatUNAMwithDr. JorgeMorales-Montor,aresearchgroup withwhichshecurrentlycollaborates researchingtheinfiltratingimmunecells andtheiralterationsbyendocrinedisruptor compoundsinpatientswithbreastcancer.
Affiliationsandexpertise
Dr.MarianaSegovia-Mendozahasextensiveexpertiseinthesubjectofcancer,especiallyinbreastcancerandhormones.She belongstotheNationalSystemofResearchersinMexicoandtodate,shehasbeen promotedtoLevelI.Atthemoment,sheisan AssociateProfessoroftheEndocrinology LaboratoryoftheFacultyofMedicinefrom theUniversidadNacionalAuto ´ nomade Mexico(UNAM).
Preface
Thisbookisavaluablesourceforcancer researchers,medicaldoctors,clinicians,and severalmembersofbiomedicalfieldwho needtounderstandthemechanismstofight resistancetoimmunotherapyincancer.This bookaddressesthefunctioningofdifferent signalingpathways,themodificationof themetabolismoftheimmunesystemcells, andthemodificationofchemicalcompoundswithestrogenicactivityinvolved inthegenerationofresistancetoimmune therapies.Thediscussionsareintendedto provideanunderstandingtobroadenthe landscapeforthecreationofdifferenttherapeuticstrategiesforcancer.
Immunetoleranceisthestateinwhich theimmunesystemdoesnotgeneratearesponsetowardotherwiseimmunogenicantigens.Toleranceiscrucialforlife,anda failuretotolerateleadstoautoimmunediseases.However,therearemomentswhen ourowncellshappentobethedisease,as withcancer.Tolerancemaybeachievedby preventingautoreactiveclonesfrommaturing,earlyintheirdevelopment,orbyeither eliminatingorsuppressingthemifthey reachtheperiphery.Palacios-Arreolaand Nava-Castrodescribethebasicmechanism mediatingthoseprocesses,namely,clonal deletion,anergyinduction,immunomodulatorycytokines,andregulatorycells.They concludebycommentingontheimmune recognitionofcancercellsandwhytoleranceisatargetforimmunotherapy. Segovia-Mendozaetal.dealwiththeresistanceofbreastcancertherapy.Itisacritical problemthatisnotfullyunderstood.Inthis sense,themolecularclassificationofthis
pathologydeterminesthetreatmentthat thepatientneeds.Differentimmuneand nonimmunetherapieshavebeenprovided forthispathology.Inthisregard,intheir chapter,theycompileanddescribethe useofimmuneclinicaloptionssuchas immunoconjugatesasanalternativefor avoidingbreastcancer resistancetoconventionaltherapy.Inaddition,theirworkisfocusedonaddressingtheinvitroapproaches untilclinicalstudiesabouttheeffectsof thesedrugsinbreastcancerareavailable. Also,inregardtobreastcancer,Gomez-De Leonmentionthatthemajorityofimmunotherapeuticapproacheshavefocusedonthe postoperativesetting;nevertheless,strategiesthatutilizeautologoustumorsarethe mostpromisingoftheimmunotherapeutic approaches,generatingaresponseagainst ahostofrelevanttumorantigens.Even more,benefitsofsystemicintravenous therapieshavebeenobservedonlyina smallpopulationofpatientsandhavebeen associatedwithtoxicityprofiles,which aresometimesverysevere.Inthischapter, theauthorsthoroughlyresumetheintratumoralimmunotherapeuticapproaches thathavebeensuccessfulintheinhibition oftumoralgrowthand/ormetastasisin differenttypesofcancer,payingspecial attentiontothedifferentdeliverysystems thathavebeendeveloped.Anotherhottopic incancerimmunotherapyisadoptivecell therapy(ACT).Volpedoetal.suggeststhat itisapromisingcancertherapyintermsof safetyandefficacyinthattheexpressionof FasLbytherapeuticlymphocytescaninduce apoptosisinFas-expressingtumorcells.
However,malignantcellscanadaptbydecreasingFastoescapefromtherapeuticlymphocytesandincreasingFasLexpressionto induceapoptosisofimmunecells,thereby mountingresistancetoACT.Toovercome thisproblem,theexpressionofFasandFasL canbemodulatedinthetumormicroenvironmenttoimmunosensitizetumorcells forACT-killing.Thiscombinedstrategyrepresentshighercost-effectivenessforcancer patients.
Prado-Garcı´aetal.mentionthatTcellsare essentialfortheimmuneresponseagainsttumorcells;inaddition,immunotherapies suchasimmunecheckpointblockade(ICB), adoptiveTcelltherapy,andCAR(Chimeric antigenreceptor)Tcellsrelyonthesecellsto triggertheeliminationoftumorcells.Inordertoexerttheireffectorfunctions,Tcells dependonmetabolismtoobtainenergyin theformofATPandmetabolitesthatare usedformacromolecularbiosynthesis.However,tumorcellsreprogramtheirmetabolismtosurviveandproliferate,whichhas deleteriousconsequencesonTcellmetabolism.Theauthorsdiscusssomepotential strategiesthatmayrestoretheTcelleffector functionbyenhancingTcellmetabolism.On theotherhand,Ostoa-Salomamentionsthat breastcanceristhemostcommoncancerin womenworldwide,andtherefore,research aimedatfindingwaysofearlydetectionof thisdiseaseassumesgreatimportance.Tools thatcontributetotherecognitionofcancer warningsignscanleadtoearlydiagnosis inahealthypopulationtoidentifypeople withthediseaseataninitialstagewhen symptomsarenotyetapparent.Earlydetectionwillincreasethesurvivalrateofpatients and,therefore,aneffectivetreatmentoption tofightthedisease;hecontinuestodescribe theadvantagesofIgM,intheirinnateform callednaturalIgM,toidentifytumor antigensinordertofindacandidateasan earlydiagnostictoolforbreastcancer.
Furthermore,questionsintheprecancerous conditionshouldbeconsidered:Isitpossible toidentifyanddifferentiatetheantigensrecognizedbybothIgMandIgGanddetermine whichimmunoglobulinisbestforidentifyingantigensinearlystages?Howwouldit betherecognitionofIgMtowardtumorantigensinthemiddleofageneticbackground associatedwithresistanceand/orsusceptibility?BymeasuringthepatternofIgMrecognitionoftumorantigens,woulditbe possibletodifferentiatewhichindividuals aremoresusceptibleandwhicharelesssusceptible?Andtherefore,bymeansofIgM, couldantigensassociatedwithsusceptibility and/orresistancetobreastcancerberecognized?Onanothertopic,Terrazasetal.term inflammationincolorectalcancerasa double-edgedsword.Theymentionthatin thepasttwodecades,acloserelationshipbetweeninflammationandcarcinogenesishas beendescribed.Infact,since2011,inflammationhasbeenconsideredasoneoftheten hallmarksofcancer.However,naturalselectiondidnotevolveinflammationtocause troublesanddiseasestoourbody.Bothtypes ofinflammation,acuteandchronic,arenaturaleventsorchestratedbytheimmunesystemtogenerateprotectionagainstinfectious andnoninfectiousinsults,includingcolorectalcancer(CRC).Strongevidenceinhumans andsomeanimalmodelsofCRCindicates thattheabsenceofmoleculesassociatedwith inflammationinducesanincreasednumber oftumorsandareductionofapoptosis, suggestingthatinflammationisinvolvedin protectionwhenthetumorhasbeen established.However,anotherlineofevidence,alsowellsupported,suggeststhat theinflammatoryprocessesduringcancer development,especiallyinCRC,arehighly undesirablebecauseitacceleratesinmany casesthetumorgrowth.Therefore,many questionsariseabouttherelationshipbetweeninflammationandCRC:Whichare
thestepsanddecisionstakenbytheimmune systemtoguidetheinflammationtofavor CRCdevelopment?Ormaybe,isinflammationaprocessinvolvedinprotectionagainst CRCestablishment?Thebalancebetweeninflammation,itscausesandcheckpointsare extremelyimportantduringCRCdevelopment;researchisunderwaystrivingtoanswerthesequestions.Inthischapter,we trytoestablishsomeevidencethatsuggest amajorroleforinflammationinprotection duringearlyCRCdevelopment.Theunderstandingofthecomplexrelationshipbetweeninflammationandcancermayhelp todevelopcombinatorytherapies(drugs andimmunomodulators)toblockadethe possiblecollateraldamageinducedby chronicinflammationthatfavorsCRCelimination.Also,inregardtoCRC,ithasbeen postulatedthatenvironmentalpollutionis nowadaysthefirstriskfactorassociated withthedevelopmentoflungcancer,stroke, andheartdisease.Withintheuniverseof acomplexmixofpollutantsthatshapethe environment,theimportanceofendocrinedisruptingcompounds(EDCs),suchas bisphenols,phthalates,aromaticpolycyclic hydrocarbons(AHPs)andpesticides,has beenhighlightedinrecentyearsbecauseof ourchronicandubiquitousexposition,particularlybyingestionoffoodandwater, andtheirinterferenceinhormoneandimmunefunctions.EDCsareassociatedprincipallywithbreastcancerdevelopment,but thereisapoorunderstandingoftherelationshipwithotherneoplasmssuchascolorectal cancer(CRC).Thepotentialcarcinogenic roleofEDCinthedevelopmentofCRC,focusingoninflammationandneuroendocrineimmuneregulation,isdiscussedby Rodrı´guez-Santiagoetal.Theypointoutthat theinteractionbetweeninflammatorybowel diseaseandCRCintermsofdisruptionofintestinalpermeability,dysbiosis,andimmune responseinducedbyEDCsisacrucialfactor
inCRC.Moreover,theauthorsdelveintothe neuroendocrineaxesinvolvedintheprogressionofthispathology.AlsoregardingCRC, ongoingevidencesuggestthatthesignaltransducerandactivatoroftranscription6(STAT6) playapivotalroleinCRCdevelopment.CompellingevidencefrombothhumanandexperimentalmodelsshowsthatSTAT6notonly contributestomediatingimmuneresponse, butisalsoinvolvedinthepathologyassociatedwithdiseasebyalteringtheepithelialbarrierfunction,promotingproliferationof intestinalepithelialcellsandregulatingtheexpressionofprosurvivalandprometastaticproteins.Thesestudieshaveledtotheapproachof targetingSTAT6asaneffectivetreatment strategyinalleviatingCRC.Thus,silencing orhinderingSTAT6signalingmaystrengthen thechemotherapyresponsewithpositiveeffectsinthecurrenttreatments.Therefore,the roleofSTAT6incolorectalcancerbiology anditspotentialasanewtherapeutictarget forthepreventionandtreatmentofthisdiseaseissuggestedbyLeon-Cabreraetal.Moreover,macrophagemigrationinhibitoryfactor (MIF)isapleiotropicproteinwithcytokine andchemokinepropertiesthatregulatesadiverserangeofphysiologicalfunctionsrelated toinnateimmunity,inflammation,and glucocorticoid-mediatedimmunosuppressionandishighlyexpressedbycancercells, throughwhichitaffectsangiogenesis,tumor growth,andmetastasis.TheroleofMIFincolorectalcancer(CRC)isunderscoredbydata showingthatitsoverexpressioninthechronic stagesofCRCisassociatedwithclinical severity.ThespecificfunctionsofMIFare nowbeingdefinedinCRC,andMIF-targeted biologictherapeuticsareinearly-stagetrials. Rodrı´guez-Sosaetal.summarizethecurrent knowledgeabouttheroleofMIFincancer withspecialemphasisonCRC.
Antibodytherapeuticshavebeenatthe heartoftransformativecancertreatmentfor morethan20years,firstwithantibodies
directlytargetingthetumorandmorerecentlywithimmunecheckpointblockade. Despitetheirimpactandwidespreadutilization,antibodytherapymechanismsofaction andfactorsgoverningresponseorresistance inpatientsarestillpoorlyunderstood.One aspectthathasemergedasimportantfor allclinicallydevelopedantibodiesisantibodyFcinteractionswithFcγ receptors. AntibodyFcactstoconnectthespecificity ofantibodytothepoweroftheinnateimmunesystemandensuingadaptiveimmunity.Whathasbecomeclearisthatinthe contextofbothdirecttumortargetingand ICBmAb,theseinteractionscanbepivotal totherapeuticactivityandsurvival.Through improvedunderstandingandevolvingstrategiesofFc-engineering,FcγR-blockade,and pharmacologicalmodulationofimmune effectorcellFcγRexpression,weareatthe dawnofharnessingthepowerofalready clinicallyvalidatedandnewclassesof antibody-basedcancerimmunotherapeutics, ascommentedbyFrendeusetal.Theypoint outthatthecurrentimpactandconsequence oftheproperinteractionoftheFc:Fcγ receptoranditsrelationtotheantibodyefficacy andresistance.Inaddition,theydiscussthe developmentofnovelclassesofantibodies asgreatstrategiestoenhancethepatientresponsesandovercomethedrugresistance. Finally,Garay-Canalesetal.mentionthat thecommoncancertherapyincludessurgery,radiotherapy,andchemotherapy;these techniqueshavesomedisadvantagessuchas lackofspecificity,causingsideeffects,and thepossibilityofrelapse.Thenoveldesign ofspecific,nontoxictherapiesforcancerrequireanin-depthknowledgeofthebiology andthemoleculesinvolved,whichwouldresultinabetteroutcomeforpatients.Thematrixmetalloproteinases(MMPs)areafamily ofzinc-dependentendopeptidases;someof themajorsubstratesarethecomponentsof
theextracellularmatrix(ECM).MMPsare responsibleforregulatingnumerousphysiologicalandpathologicaleventsincluding bonedevelopment,woundrepair,and differentstagesincarcinogenesis.Therefore, theseenzymesrepresenthighlyrelevant targetsforcancertherapy.Overexpression ofMMPsiswelldocumentedinmosttypes ofcancer;upregulatedexpressionispresent notonlyincancercells,butalsoinstroma cells,whichmodifyandregulatethetumor microenvironment.Tobreakthecancer tolerance,theydiscusstheevolutionofsome strategies:FirsteffortsusingMMPswere addressedtoinhibitthecatalyticsiteorthe bindingzincdomain;althoughseveral chemicalinhibitorsweresynthesized,poor specificitytotargetonlycancercellswas achieved,andnoneofthempassedhuman clinicaltrials.Then,studiesofcrystal structure,phagedisplay,andproductionof monoclonalantibodiesrevealedspecific epitopesordomainswithintheMMPs,these crypticsitesarehelpfultodesignnewtargets. Onenovelstrategyisthedrugdelivery systems(DDS);thisstrategyusestheupregulatedexpressionofMMPsincancercells andisbasedonthespecificityofsensitive MMPsubstratesormonoclonalantibodies attachedtoahighlytoxicdrugthatwillbe “activatedorreleased”onlyinthepresence oftheselectedMMP.Altogether,knowing thefeaturesoftheMMPs,itispossibleto designmorespecificandlesstoxictherapies forseveraltypesofcancerandcombining thesestrategieswithstandardtherapies,we couldachievethegoalofbettersurvivalrate forcancerpatients.
Thus,thebookitisanactualized,up-todatecompilationthatintendstobeofuse toallpeopleinvolvedintheworldofcancer.
JorgeMorales-Montor MarianaSegovia-Mendoza
Contributors
StephenA.Beers AntibodyandVaccineGroup, CentreforCancerImmunology,Universityof SouthamptonFacultyofMedicine,Southampton,UnitedKingdom
DanielaAlejandraCastro-Flores Departamento deEnfermedadesCronico-Degenerativas, InstitutoNacionaldeEnfermedades Respiratorias,“IsmaelCosioVillegas”,Ciudad deMexico,Mexico
MariannadeCarvalhoClı ´ maco Institutode Ci^ enciasBiolo ´ gicas,Departamentode Parasitologia,UniversidadeFederaldeMinas Gerais,BeloHorizonte,MinasGerais,Brazil
YaelDelgado-Ramirez UnidaddeInvestigacio ´ n Biomedica,UniversidadNacionalAuto ´ noma deMexico,Tlalnepantla,Mexico
LauraDı´az-Alvarez PosgradoenCiencias Biolo ´ gicas,UniversidadNacionalAuto ´ noma deMexico,CiudadUniversitaria,Ciudadde Mexico,Mexico
BjornFrendeus BioInventInternationalAB, Lund,Sweden
ClaudiaA.Garay-Canales Departamentode Inmunologı´a,InstitutodeInvestigaciones Biomedicas,UniversidadNacionalAuto ´ noma deMexico,CiudaddeMexico,Mexico
RocioGarcı´a-Becerra Departamentode Biologı´aMolecularyBiotecnologı´a,Instituto deInvestigacionesBiomedicas,Universidad NacionalAuto ´ nomadeMexico,Ciudadde Mexico,Mexico
AnaP.Garcı´a-Garcı ´ a Unidad deBiomedicina, FacultaddeEstudiosSuperioresIztacala, UniversidadNacionalAuto ´ nomadeMexico, Tlalnepantla,Mexico
CarmenT.GomezdeLeon Departamentode
Inmunologı´a,InstitutodeInvestigaciones Biomedicas,UniversidadNacionalAuto ´ noma deMexico,CiudaddeMexico,Mexico
ImeldaJua ´ rez-Avelar UnidaddeBiomedicina, FacultaddeEstudiosSuperioresIztacala, UniversidadNacionalAuto ´ nomadeMexico, Tlalnepantla,Mexico
CristinaLemini Departamentode Farmacologı´a,FacultaddeMedicina, UniversidadNacionalAuto ´ nomadeMexico, CiudaddeMexico,Mexico
SoniaLeon-Cabrera UnidaddeInvestigacio ´ n Biomedica;EscueladeMedicina,Facultadde EstudiosSuperioresIztacala,Universidad NacionalAuto ´ nomadeMexico,Tlalnepantla, Mexico
GeorginaI.Lopez-Cortes Departamentode Inmunologı´a,InstitutodeInvestigaciones Biomedicas,UniversidadNacionalAuto ´ noma deMexico,CiudaddeMexico,Mexico
ItzelMedina-Andrade LaboratorioNacionalen Salud:Diagno ´ sticoMolecularyEfecto AmbientalenEnfermedadesCro ´ nicodegenerativas;UnidaddeBiomedicina, FacultaddeEstudiosSuperioresIztacala, Universidad NacionalAuto ´ nomadeMexico, Tlalnepantla,Mexico
JorgeMorales-Montor Departamentode Inmunologı´a,InstitutodeInvestigaciones Biomedicas,UniversidadNacionalAuto ´ noma deMexico,CiudaddeMexico,Mexico
KarenElizabethNava-Castro Departamentode MutagenesisyGenotoxicidadAmbientales, CentrodeCienciasdelaAtmo ´ sfera, UniversidadNacionalAuto ´ nomadeMexico, CiudaddeMexico,Mexico
JonadabE.Olguı ´ n LaboratorioNacionalen Salud:Diagno ´ sticoMolecularyEfectoAmbiental enEnfermedadesCro ´ nico-degenerativas; UnidaddeBiomedicina,FacultaddeEstudios SuperioresIztacala,UniversidadNacional Auto ´ nomadeMexico,Tlalnepantla,Mexico
PedroOstoa-Saloma Departamentode Inmunologı´a,InstitutodeInvestigaciones Biomedicas,UniversidadNacionalAuto ´ noma deMexico,CiudaddeMexico,Mexico
ThaliaPacheco-Ferna ´ ndez Unidadde Biomedicina,FacultaddeEstudiosSuperiores Iztacala,UniversidadNacionalAuto ´ nomade Mexico,Tlalnepantla,Mexico
M.IsabelPalacios-Arreola Departamentode MutagenesisyGenotoxicidadAmbientales, CentrodeCienciasdelaAtmo ´ sfera, UniversidadNacionalAuto ´ nomadeMexico, CiudaddeMexico,Mexico
HeribertoPrado-Garcia Departamentode EnfermedadesCronico-Degenerativas, InstitutoNacionaldeEnfermedades Respiratorias,“IsmaelCosioVillegas”,Ciudad deMexico,Mexico
TonathiuRodrı ´ guez UnidaddeBiomedicina, FacultaddeEstudiosSuperioresIztacala, UniversidadNacionalAuto ´ nomadeMexico, Tlalnepantla,Mexico
YairRodriguez-Santiago Departamentode Inmunologı´a,InstitutodeInvestigaciones Biomedicas,UniversidadNacionalAuto ´ noma deMexico,CiudaddeMexico,Mexico
MiriamRodrı´guez-Sosa UnidaddeBiomedicina,FacultaddeEstudiosSuperiores
Iztacala,UniversidadNacionalAuto ´ nomade Mexico,Tlalnepantla,Mexico
SusanaRomero-Garcia Departamentode EnfermedadesCronico-Degenerativas, Instituto NacionaldeEnfermedades Respiratorias,“IsmaelCosioVillegas”,Ciudad deMexico,Mexico
AnaCatalinaRiveraRugeles UnidaddeInvestigacio ´ nBiomedica,UniversidadNacional Auto ´ nomadeMexico,Tlalnepantla,Mexico
AbhayR.Satoskar DepartmentofPathology, TheOhioStateUniversityMedicalCenter;DepartmentofMicrobiology,TheOhioStateUniversity,Columbus,OH,UnitedStates
MarianaSegovia-Mendoza Departamentode Farmacologı´a,FacultaddeMedicina, UniversidadNacionalAuto ´ nomadeMexico, CiudaddeMexico,Mexico
LuisI.Terrazas LaboratorioNacionalenSalud: Diagno ´ sticoMolecularyEfectoAmbientalen EnfermedadesCro ´ nico-degenerativas;Unidad deBiomedicina,FacultaddeEstudios SuperioresIztacala,UniversidadNacional Auto ´ nomadeMexico,Tlalnepantla,Mexico
GretaVolpedo DepartmentofPathology,The OhioStateUniversityMedicalCenter;DepartmentofMicrobiology,TheOhioStateUniversity,Columbus,OH,UnitedStates
Cancervsimmunetolerance—The challengeoffighting“self”
M.IsabelPalacios-ArreolaandKarenElizabethNava-Castro
DepartamentodeMutagenesisyGenotoxicidadAmbientales,CentrodeCienciasdelaAtmo ´ sfera, UniversidadNacionalAuto ´ nomadeMexico,CiudaddeMexico,Mexico
Abstract
Immunetoleranceisthestateinwhichtheimmunesystemdoesnotgeneratearesponsetowardsotherwise immunogenicantigens.Toleranceiscrucialforlifeanditsfailuresleadtoautoimmunediseases.Tolerance maybeachievedbypreventingautoreactiveclonesfrommaturing,earlyintheirdevelopment,oreithereliminatingorsuppressingthemiftheyreachperiphery.However,therearemomentswhenourowncellshappen tobethedisease,likewithcancer.Herein,wedescribethebasicmechanismmediatingthoseprocesses,namely clonaldeletion,anergyinduction,immunomodulatorycytokines,andregulatorycells.Finally,wecomment ontheimmunerecognitionofcancercellsandwhytoleranceisatargetforimmunotherapy.
Abbreviations
AIRE autoimmuneregulator
APCs antigen-presentingcells
BCR Bcellreceptor
cAMP cyclicadenosinemonophosphate
CTLA-4 cytotoxicTlymphocyteantigen-4
DCs dendriticcells
IFN-γ interferongamma
IL interleukin
iTreg inducedregulatoryTcell
MHC majorhistocompatibilitycomplex
nTreg naturalregulatoryTcell
PD-1 programmeddeath1receptor
STAT signaltransducerandactivatoroftranscription
TCR Tcellreceptor
TFG-β transforminggrowthfactorbeta
ImmunotherapyinResistantCancer: FromtheLabBenchWorktoItsClinicalPerspectives
2021ElsevierInc.Allrightsreserved. https://doi.org/10.1016/B978-0-12-822028-3.00018-2
TGF-βRI TFG-β receptorI
TGF-βRII TFG-β receptorII
Th Thelperlymphocyte
TNF-α tumornecrosisfactoralpha
Conflictofinterest
Nopotentialconflictsofinterestweredisclosedbytheauthors.
Introduction
Immunetolerance
Sincetheearly1900s,itwasobservedthattheimmunesystemwasabletodistinguishself fromnon-self.Ehrlichwasoneofthefirstinnoticingthatimmunesystemwouldrespondto everythingthatwasinjectedtoanindividual,includingcellsfromanotherindividualfrom thesamespecies,butnottocellsoftheirownbody [1].Beforethis,itwasconsideredobvious thattheimmunesystemdoesnotattackitsowncellsandtissues,butithasbeendemonstrated thatthisisacomplexwell-orchestratedphenomenonthatisactivelypursuedtomaintain homeostasis.
Immunetoleranceisastateinwhichtheimmunesystemdoesnotgeneratearesponsetowardsotherwiseimmunogenicantigens.Buthowdoestheimmunesystemgettoknowand recognizeitself?Thereisnogeneralruleastowhichantigenstheimmunesystemistolerant, immunetoleranceisshapedthroughoutdevelopmentandduringtheadultlifeandrelieson multiplemechanisms.
Toleranceisindispensableforlifeandfailuresinitleadtoautoimmunedisease.However, asthisbookwilldiscuss,therearemomentswhenourowncellshappentobethedisease.This isthecasewithcancer,andtoleranceimpliesthattheimmunesystemisconditionednotto attackthoseowncells,leadingtoapoorimmuneantitumoralresponse.Thisistheissuethat immunotherapytriestoovercome.
Mechanismsofimmunetolerance
Whentalkingabouttheimmunesystem,therearetwobasicbranches:innateandadaptive immunity.Innateimmuneactivationisbasedontherecognitionofpathogen-associatedmoleculeswhichareevolutivelyabsentinourtissuesordanger-associatedmolecules,whichare commontoallindividualsofaspecies,genre,andeventaxonomicalfamilies.Onthecontrary, adaptiveimmuneactivationismuchmorediverse,basedontherecognitionofaninfinite numberofpossibleantigens.Amongallthosepossibleantigensthattheadaptiveimmune systemmayrecognize,theremaybeantigenspresentintheowntissues,thatis,self-antigens orautoantigens.Forthisreason,immunetoleranceisgenerallyfocusedonTandBcells,althoughsomemechanismsinvolvealsocellsfromtheinnateimmunesystem.
Therearetwomainwaystoachieveimmunetolerance,oneistoavoidthegenerationor maturationofautoreactiveTorBcells,whichisdeemedascentraltolerance,andtheotheris
FIG.1 Mechanismsforimmunetolerance.Centralimmunetoleranceoccursinprimarylymphoidorgans,before thecellsentertheperiphery.TandBlymphoidlineagesundergoclonaldeletionofautoreactivecellsduringtheir development;additionally,somesurvivingautoreactiveTcellsmaydevelopintonTregs.Peripheralimmunetoleranceallowsformodulationand/orinhibitionofimmunecellsonceintheperiphery.Thisisachievedthroughclonal deletionandanergyofTandBcells,thesecretionofinhibitorycytokines,andactionofTregs.
toeliminateorsuppressthoseautoreactivecellsthatmighthavescapedthefirstmechanisms, whichistermedperipheraltolerance(see Fig.1).
Centraltolerance
CentraltoleranceisbasedonthepreventionanddepletionofautoreactiveTandBcells. Thedevelopmentandmaturationofthosecelllineagesaredifferentandsoarethemechanismsusedtoconfertolerance.
ImmatureTcellprogenitorsemergefromthebonemarrowandmigratetothethymus wheretheyarriveinaso-calleddouble-negativephenotype,lackingbothCD4andCD8 co-receptorsandTcellreceptor(TCR).Asthymocytes(developingTlymphocytes)mature, theyacquirebothCD4andCD8moleculesandapreliminaryversionoftheTCRandthen theyundergoaselectionprocessinwhichTCR’sabilitytobindMHCmoleculesistested [2].ItisimportanttonotethatMHCmoleculesexpressedoncorticalthymicepithelialcells
displayself-antigens [3].AfunctionalTCRmustbeabletointeractwithMHCmolecules,so thatthymocytesthatarenotabletointeractorthosewhichinteracttooweaklyreceivenosurvivalsignalanddie.IfathymocyteisabletointeractwithMHCclassImolecules(usingCD8 co-receptor),itispositivelyselectedandcommitstothecytotoxicCD8+ lineage,whilethe CD4+ lineageisdefinedbyTCR’saffinitytoMHCclassIImoleculeswithCD4asco-receptor. However,ifTCRinteractionwithMCHmolecules(displayingself-antigens)istoostrong, apoptosisistriggered,thisiscallednegativeselection [2].
ItwouldappearasthisfirstnegativeselectionmanagedtoeliminateautoreactiveTcells, butcorticalthymicepithelialcellsareonlyabletodisplayself-antigenspresentin themselves [3].Asdifferentiatedcells,theydonotexpresseveryproteinencodedinthe genome.Furtherintheirdevelopingpath,lineage-committed,singlepositivethymocytes enterthethymusmedulla,wheretheyinteractwithdendriticcells(DCs)andmedullary thymicepithelialcellswhichdisplayawiderrepertoireofself-antigens [2].Whatallowsthis widerrepertoireisatranscriptionfactornamedAIRE(fromautoimmuneregulator), whichinducesthetranscriptionofawidearrayoftissue-specificantigens [4].Onceagain, ifathymocyteinteractstoostronglywithanyMHCmoleculedisplayinganautoantigen, itwillbenegativelyselectedandconductedtoeitherdeathoranaturalregulatory Tphenotype(nTreg).
UnlikeTcells,Blymphocytesfullydevelopinthebonemarrow.WhetherBcellsundergo positiveselectionprocessisstillunclear,butnegativeselectiondoesoccur.ImmatureBcells interactwithbonemarrowcellsexpressingso-calledhousekeepingmolecules(proteins,carbohydrates,orglycolipids);iftheirBcellreceptor(BCR)recognizesoneofthosemolecules,it receivesasignaltoholdmaturationandundergoesa“secondchance”BCRrecombination [5] InthecasethatthissecondrearrangedBCRisstillautoreactive,thecellreceivesaproapoptoticsignal [6].
Peripheraltolerance
Despitethenegativeselectionprocesses,someautoreactiveclonesmaystillentertheperiphery;however,therearewaystoeliminatethemorsuppresstheiractivity.Peripheraltoleranceisachievedbymultiplemechanisms,includingperipheralclonaldeletion,anergy induction,immunomodulatorycytokines,andregulatorycells [1,7].
Thefirstthreemechanismsforperipheraltolerancerelyonthethree-signalparadigmfor lymphocyteactivation.PeripheralTandBlymphocytesdonotacquireeffectorfunctionsby justencounteringtheirantigen,butrequiredifferentsignalstofullyactivateandproliferate. Thoserequisitesarereferredtoasthethree-signalparadigm [8].ThefirstsignalisthepresentationoftheantigeninthecontextofMHCmolecules,whichinteractwiththeTCR.Thesecondsignalisprovidedbyco-stimulatorymoleculesexpressedbyantigen-presentingcells (APCs)orhelperTcells.Themainco-stimulatorymoleculeforTcellsisCD28whoseAPC counterpartsareB7-1(CD80)andB7-2(CD86),whileBcellprimaryco-stimulatorymolecule isCD40whichbindstoCD40LexpressedbyhelperTcells(Th) [9,10].TheexpressionofcostimulatorymoleculesinAPCsiscontext-dependentanditsupregulationoftendependson therecognitionofpathogen-associatedordanger-associatedmolecules [11,12].Signalsderivedfromco-stimulationpreventapoptosis(inducingtheantiapoptoticBcl-xl),thus
increasingactivationpathwaysandpromotingcytokineproductionofactivatedcells [9,10] Thethirdsignalisprovidedbycytokinesproducedbyinnateimmunecellsuponactivation [8].Besidesaidingintheactivation,cytokinesalsoshapethekindofadaptiveimmune responsegenerated.
Peripheralclonaldeletion
PeripheralclonaldeletionofTcellsoccursinthelymphnodes,whereTcellsinteractwith immatureDCsthatroutinelytakeupandprocessapoptoticcellswhichleadstoautoantigen presentation.Sincethereisnopathogeninfectionordangersignals,thoseDCsexpressvery lowlevelsofco-stimulatorymolecules,sothatthesecondsignalisdeficient [1].Thisresultsin theactivationofapoptoticFasandBimpathways [13] thatleadtoapoptosisintheabsenceof antiapoptoticBcl-xlsignaling [9].
Bcellperipheralclonaldeletionalsooccurs,butseemstobeamoreplasticphenomenon.It hasbeendemonstratedthatautoreactiveBclonesthatpersistintheperipherymaybedeleted uponencounterofhighlymultivalentmembrane-boundantigens [14],butrecentevidence suggeststhatmultipleantigenencountersmayberequiredforefficientdeletionofthose autoreactiveclones;otherwise,thoseclonesmaypersist,althoughfunctionallyanergic,with ashortlifespan [15]
Anergyinduction
Anergyisamechanisminwhichlymphocytesarefunctionallyinactivatedfollowing suboptimalantigenencounter,butremainaliveforacertainperiodoftimeina hyporesponsivestate [16],withdefectivephospholipaseactivationandintracellularcalcium mobilization [17].Asdescribedearlier,co-stimulationprovidessurvivalsignalsandactivates multiplepathwaysforproperactivation.Nevertheless,suboptimalco-stimulationmayprovidesufficientantiapoptoticsignals,butnotenoughactivationones.
Interestingly,co-stimulatorymoleculesnotonlyprovidepositivesignaling,someprovide negativesecondsignalsthatinhibitTcellresponses,mediatingtolerance [13].Oneofthemost importantnegativeco-stimulatorymoleculesistheprogrammeddeath1receptor(PD-1), whichisexpressedonT,B,andmyeloidcells [7] andbindstoPD-L1andPD-L2ligands.Upon ligandbinding,PD-1mediatestheinhibitionofPI3KandAktpathways,preventingTcell properactivation [18].
Anotherkeynegativeco-stimulatorymoleculeknowntoinduceanergyisCTLA-4,which alsobindstoB7moleculesbutinducesacompletelydifferentsignalingthatpreventscyclecell progression [13].CTLA-4inhibitsCD28-dependentTcellactivation,cellcycleprogression, andIL-2production [19,20].TheroleofCTLA-4inanergyisalsorelatedtotheexpression ofgeneslike Cbl-b, p25Kipl, Dgkz, Itch, NFAT1,and Grail [21].
RegardingautoreactiveBcells,ifaviditytoself-antigensissignificantbuttoolowtoinduce clonaldeletion,thosecellsmaybemaintainedintheperipheryinananergicstate,unableto mobilizecalcium,upregulateactivationmarkers,orproliferate [22].Anergyisachievedby chronicbindingofantigenintheabsenceofsecondarysignals(co-stimulationbyTh), pathogen-ordanger-associatedsignals [22].However,anergyisnotpermanentanddependentsoncontinuedoccupancyofantigenreceptorsandremovalofantigenresultsintherestorationofresponsiveness [23].
Inhibitorycytokines
Cytokinesarekeymoleculesthatshapeimmuneresponse,eitherbystimulatingor byinhibitingcertaintypesofresponse.Somecytokinesareconsideredparticularly inhibitory:IL-10andTFG-β.ThosecytokinesareproducedprimarilybyregulatoryTcells, butmayalsobesecretedbyanergicTcells [1].
Uponbindingtoitsreceptor,IL-10signalingactivatestheJak-STATpathway,particularly STAT3 [24].OneofthemaineffectsofIL-10isthesuppressionofTLRsignaling,whichiscrucialforAPCactivation [25].ThiscytokinealsodownregulatestheexpressionofproinflammatorycytokineslikeTNF-α,whichexertsstimulatoryeffectsonAPCs [25],aswell asIL-1α,IL-1β,IL-6,andIL-12 [26].IL-10alsointerfereswithIFN-γ signaling,whichisnecessaryfortheexpressionofMHCclassIIandco-stimulatorymolecules,pro-inflammatory cytokineproduction,andproperactivationofmonocyte-macrophages [27].
TGF-β isapleiotropicfamilyofcytokinesexpressedbymanyimmuneandnonimmune cells [28].Itregulatesmultipleprocesses,fromembriogenesistocarcinogenesis [29] andof courseimmunetolerance.TGF-β bindstoatetramericreceptorcomposedoftwoTGF-βRI andtwoTGF-βRIImolecules,whichresultsintheactivationofSmadtranscriptionfactors [29].Oneofthetolerogenicmechanismsofthiscytokineistheinhibitionofbothhelper andcytotoxicTlymphocytes,whichismediatedbythesuppressionorIL-2production, downregulationofc-myc,andupregulationofcyclin-dependentkinaseinhibitors [28].RegardingcytotoxicTlymphocytes,theyarefurtherregulatedbyTGF-β throughtheinhibition ofperforinandIFN-γ productionandmayevenbesubjecttoapoptosis,sinceTGF-β upregulatesthepro-apoptoticproteinBim [28].AnothermechanismbywhichTGF-β promotesimmunetoleranceistheinductionofregulatoryTcells(Tregs).Earlyduringnegative selectioninthethymus,TGF-β isabletoinduceFoxp3expression [29],favoringthenTreg phenotype.Later,intheperiphery,TGF-β promotestheconversionofnaıveCD4+ Tcellsinto inducedTregs(iTregs),upregulatingFoxp3expression [28]
Regulatorycells
RegulatoryTcells(Tregs)accountforapproximately5%–10%ofperipheralCD4+ Tcells andmodulateimmuneresponsethroughsuppressivemechanisms [30].Nowadays,itis recognizedthattherearedifferenttypesofTregs,buttheyaretypicallycharacterizedby theexpressionofFoxp3and/orhighexpressionoftheIL-2receptor,CD25 [31].Tregshave beenreportedtoexertinhibitoryeffectsonTcells,Bcells,APCs,andotherimmunecelltypes, suchasNK,NKT,mastcells,andosteoblasts [32,33].Tregssuppressormodulateimmune responsethroughseveralmechanisms,includingcytolysis,modulationofDCmaturation orfunction,metabolicdisruption,andtheproductionofinhibitorycytokines [34]
Cytolysisisacontact-dependentmechanismofTregsuppressionandisbasedonthe secretionofperforinandgranzymeA/B,leadingtoapoptosisoftargetcells [33]
TregsinhibitAPCmaturationandfunctionthroughcontact-dependentmechanismsthat involveCTLA-4,andLAG-3 [30,32].ThisresultsinAPCdownregulationofco-stimulatory molecules,mainlyCD80/CD86,whichdiminishestheabilityofAPCstoproperlyactivate othercells.
ThemoststudiedmechanismformetabolicdisruptionisIL-2deprivation.SinceTregsexpresshighlevelsofCD25,thoselymphocytesconsumegreatamountsofIL-2,whichleadsto thedepletionofthiscytokine,beingunavailableforotherTsubpopulationslikecytotoxicand
