Tumor-Induced Immune Suppression: Mechanisms and Therapeutic Reversal PDF
Preview Tumor-Induced Immune Suppression: Mechanisms and Therapeutic Reversal
Tumor-Induced Immune Suppression Dmitry I. Gabrilovich • Arthur A. Hurwitz Editors Tumor-Induced Immune Suppression Mechanisms and Therapeutic Reversal 2123 Editors DmitryI.Gabrilovich ArthurA.Hurwitz Translational TumorImmunology NPotomac TheWistarInstitute Maryland Philadelphia USA Pennsylvania USA ISBN978-1-4899-8055-7 ISBN978-1-4899-8056-4(eBook) DOI10.1007/978-1-4899-8056-4 SpringerNewYorkHeidelbergDordrechtLondon LibraryofCongressControlNumber:2014930103 © SpringerScience+BusinessMedia,LLC2014 Thisworkissubjecttocopyright.AllrightsarereservedbythePublisher,whetherthewholeorpartofthe materialisconcerned,specificallytherightsoftranslation,reprinting,reuseofillustrations,recitation, broadcasting,reproductiononmicrofilmsorinanyotherphysicalway,andtransmissionorinformation storageandretrieval,electronicadaptation,computersoftware,orbysimilarordissimilarmethodology nowknownorhereafterdeveloped.Exemptedfromthislegalreservationarebriefexcerptsinconnection withreviewsorscholarlyanalysisormaterialsuppliedspecificallyforthepurposeofbeingenteredand executed on a computer system, for exclusive use by the purchaser of the work. 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Printedonacid-freepaper SpringerispartofSpringerScience+BusinessMedia(www.springer.com) Preface Sincepublicationofthefirsteditionofthismonographthefieldoftumorimmunol- ogy and immunotherapy made tremendous progress. The second edition reflects thosechanges.Thechapterswererevisedtoreflectnewinformationandseveralnew chapterswereadded.Thedevelopmentofanyfieldofsciencefollowsspiralmotion frombasicobservationstogreaterunderstandingofmoreandmorecomplexmech- anisms.Alongthisroad,manybasicfactsarebeingrediscoveredovertime,atnew, moresophisticatedlevels. However, forpeopleoutsidethefield, thisspiralmotion isusuallylostandthemovementisoftenreminiscentofapendulum.Theperiodof enthusiasmisfollowedbywidespreaddisappointmenttobereplacedbytherenewed enthusiasm. Tumor immunology and cancer immune therapy are classic examples of this paradigm.Initialrealizationthatsomeimmunemechanismscouldbeinvolvedincon- troloftumorgrowthandhopesthatthetreatmentofcancerwithbacterialpathogens orsimplevaccinescouldcurecancermadetumorimmunologyanexcitingareaof research in the first 30 years of last century. However, the period of high expecta- tionswasfollowedbylonghiatusofskepticismorevenoblivionwhenclinicalresults did not meet expectation. Moreover, some experimental results suggested that the immunesystemwasnotinvolvedinregulationoftumorprogression. Inlate1980s,whenthenatureofsometumor-associatedantigenswasidentified andresearchersdiscoveredlimitationsoforiginalexperimentalsystemsusedtode- terminetheroleoftheimmunesystemincancer,interestinthefieldreturned.With theidentificationofmanyregulatoryactivitiesinTcellactivation,moremolecularly- targeted approaches were described. Many clinical trials were initiated and hopes forquickprogresswereagainhigh.However,atthebeginningofthiscentury,lack ofsufficientsuccessinclinicaltrialsturnedthependulumbacktoskepticism. Fortunately, this skepticism was placed in very a different environment than in previousyears.Muchmorewaslearnedaboutthemechanismsbywhichtheimmune systemrespondstotumorsandhowitisregulated.Oneoftheareasthatdeveloped fast during the last 20 years was immune suppression in cancer. Research in this field did not slow down and in recent years, has produced real pre-clinical suc- cesses. Now, the field is gaining momentum again. Interest in tumor immunology andimmunotherapyishigh,andnumerousclinicaltrialsarebeingconducted,with v vi Perface encouragingresults.ThisincludesFDAapprovalofbothaprostatecancervaccine andamonoclonalantibodywhichblocksCTLA-4-dependentinhibition.However, despitemanypositivesigns,itisclearthatthelevelofresponsesisstillratherlimited and only a fraction of the patients truly benefit from these therapies. One of the major factors that limits the effect of cancer immune therapy is the persistence of suppressivemechanismsthatariseinthetumormicroenvironment,whichlimitthe durabilityofanti-tumorimmuneresponses. Thismonographwillpresentreaderswithabroadandcomprehensiveoverviewof thesemechanisms.Theyrangefromimmunesuppressivecytokinesandmolecules expressed by tumor cells to immune suppressive T cells and myeloid cells. Each factorhasitsownhistory,elaboratepathwayandfunctionalconsequences.Thelitany ofmechanismspresentintumor-bearinghostsissopowerfulandredundant,thatit raisesaquestionhowahostcanactuallysurvivesuchanonslaught,giventheneedfor maintainingimmunitytopathogens.Importantly,itiswellknownthatneithertumor- bearingmicenorcancerpatientsareprofoundlyimmunesuppresseduntilverylatein tumorprogression.Eveninthatsituation,itisnotclearwhethertheseconsequences areduetospecificimmunesuppressivemechanismsormetabolicchangesassociated withtumor-inducedcachexia.Patientsdon’tsufferfromopportunisticinfectionsand couldbeimmunized,albeitwithsomedifficulties,againstviralpathogens. Itseemsthattherearetwopossibleexplanationforthisparadox.Oneisthatthere isastrongcompartmentalizationofimmunesuppressionassociatedwithcancer.The tumorsiteprovidesaprofoundimmunesuppressivemicroenvironment,whereasin peripherallymphoidorgans,non-specificsuppressionisratherlimitedandthemain operationalmechanismistumor-specificimmunetolerance.Severalchaptersinthis bookwilldiscusstheseissues. However,therecouldbeanotherexplanation.Itispossiblethatvariousimmune suppressivefactorsarenotthatredundantafterallandinstead,areessentiallytumor- specific.Inthisscenario,atumorhasa“driver”immunesuppressivemechanismthat determines the outcome of the response and “passenger” mechanisms, which may be present but not critical. One example is the role of myeloid-derived suppressor cells(MDSC)andregulatoryT(Treg)cellsinmelanoma.IntheB16F10melanoma model,TregcellsplayaprominentrolewhereasMDSCsappeartobea“passenger” factor.ThesituationisreversedintheRettransgene-inducedmelanomamodel,where MDSCarethecritical“driver”factordeterminingthesuppressivemechanism.This paradigmcanbeobservedinothertumormodelswheredifferentimmunesuppressive factorsmayexertdifferentroles. Immune suppressive factors are attractive therapeutic targets with a goal of boosting immune responses and enhancing antitumor activity. However, universal approachestotherapeuticcorrectionofthesituationmaybepronetofailure.There is also a risk of targeting redundant or inconsequential suppressive mechanisms whichmightalsohaveadverseeffectstoimmunotherapy.Weneedtoapproachthis therapeutic intervention with open eyes to avoid mistakes made in previous years. Thereforefuturestudiesshouldaddressseveralmajorquestions. Perface vii (cid:129) Thereisaneedtodetermine“driver”immunesuppressionfactorsforeachtype of tumor and specific factors that could cause this. This may be used for more precisetargeting; (cid:129) Itmayworthconsideringthecreationofastandarddiagnosticpanel,wheremajor factorsofimmunesuppressionaretestedineachparticulartumor; (cid:129) Compensatory changes need to be monitored, with consideration of targeting multiplemechanismsasnecessary; (cid:129) Monitoringdifferentsuppressivemechanismsduringrelapse. In recent years, a new paradigm of cancer treatment was developed. It suggests that conventional cancer therapy (radiation, chemotherapy) can synergize with immune-basedtherapyofcancer.Theroleofimmunesuppressivenetworksinthis combinatorialtherapyisonlybeginningtoemerge. Itistemptingtospeculatethat elimination of immune suppression could play an important role in this process. However, the results are mainly obtained in tumor-bearing mice and more work needstobedoneintheclinicalsetting, whichwillgiveamorerealisticvalidation tothehypothesis.Thefieldoftumorimmunologyisnowengagedinarenaissance, with very high hopes for successful immune therapeutics. However, in order to be successful, we need to revisit our understanding of the regulation of the tumor microenvironment.Webelievethatthismonographwillhelpreaderstodothis. Contents 1 RegulatoryTCellsandCancer .................................. 1 MaryJoTurk 2 Th17CellsinCancer ........................................... 37 ChrystalM.Paulos,MichelleH.NelsonandXue-ZhongYu 3 MastCellsandImmuneResponseinCancer ...................... 77 MarioP.ColomboandPaolaPittoni 4 Myeloid-Derived Suppressor Cells in Tumor-Induced TCellSuppressionandTolerance................................ 99 PaoloSerafiniandVincenzoBronte 5 ImmunobiologyofDendriticCellsinCancer ...................... 151 MichaelR.Shurin,AntonA.KeskinovandGurkamalS.Chatta 6 MacrophagesandTumorDevelopment ........................... 185 SuzanneOstrand-Rosenberg 7 AngiogenesisandImmuneSuppressioninCancer ................. 213 GregT.MotzandGeorgeCoukos 8 Tim-3RegulationofCancerImmunity ........................... 239 KaoriSakuishiandAnaC.Anderson 9 Transcriptional Regulation of Dendritic Cells in the Tumor Microenvironment ............................................. 263 AiminJiang,KatherineE.Stagliano,StevenM.Cuss,AshleyTriplett, ChunmeiFuandArthurA.Hurwitz 10 S100A9, Inflammation, and Regulation of Immune Suppression inCancer ..................................................... 295 ThomasCondamine,InduR.RamachandranandDmitryI.Gabrilovich ix x Contents 11 IDO in Inflammatory Programming and Immune Suppression inCancer ..................................................... 311 GeorgeC.Prendergast,CourtneySmith,SunilThomas,Laura Mandik-Nayak,LisaLaury-Kleintop,RichardMetz,AlexanderJ.Muller 12 DefiningtheFateandFunctionofEffectorTcellsThrough Galectin-1–Galectin-1Ligand-BindingInteractions:Implications inTumorImmunity ............................................ 347 CharlesJ.DimitroffandGabrielA.Rabinovich 13 Arginine Metabolism, a Major Pathway for the Suppressive FunctionofMyeloid-DerivedSuppressorCells .................... 369 PauloC.RodríguezandAugustoC.Ochoa 14 The Hypoxia-adenosinergic Immunosuppression and Redirection ofImmuneResponseinTumorMicroenvironment ................. 387 AkioOhtaandMichailSitkovsky 15 Molecular Pathways in Antigen-Presenting Cells Involved intheInductionofAntigen-specificT-cellTolerance................ 411 DavidM.Woods,AndressaLaino,AlejandroVillagra andEduardoM.Sotomayor 16 OvercomingImmuneSuppression:TherapeuticStrategiesTargeting T-CellFunctioninCancer....................................... 435 JeffreyS.Weber Index ............................................................ 463 Contributors Ana C. Anderson Center of Neurologic Diseases, Department of Neurology, BrighamandWomen’sHospital,HarvardMedicalSchool,Boston,MA,USA VincenzoBrontePathologyDepartment,VeronaUniversityHospital,Verona,Italy Gurkamal S. Chatta Virginia Mason Medical Center Cancer Institute, Seattle, WA,USA Mario P. Colombo Molecular Immunology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS “Istituto Nazionale dei Tumori”viaAmadeo,Milan,Italy ThomasCondamineTheWistarInstitute,Philadelphia,PA,USA George Coukos Ovarian Cancer Research Center, University of Pennsylvania SchoolofMedicine,Philadelphia,PA,USA StevenM.CussTumorImmunityandToleranceSection,LaboratoryofMolecular Immunoregulation, Cancer and Inflammation Program, National Cancer Institute, Frederick,MD,USA CharlesJ.DimitroffDepartmentofDermatology,BrighamandWomen’sHospital, HarvardMedicalSchool,Boston,MA,USA ChunmeiFuDepartmentofImmunology,RoswellParkCancerInstitute,Buffalo, NY,USA DmitryI.GabrilovichTheWistarInstitute,Philadelphia,PA,USA Arthur A. Hurwitz Tumor Immunity and Tolerance Section, Laboratory of MolecularImmunoregulation,CancerandInflammationProgram,NationalCancer Institute,Frederick,MD,USA AiminJiangDepartmentofImmunology, RoswellParkCancerInstitute, Buffalo, NY,USA Anton A. Keskinov Department of Pathology, University of Pittsburgh Medical Center,Pittsburgh,PA,USA xi
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