Table Of ContentTumor-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
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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
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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
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