Table Of Content1
CHAPTER
Introduction
George C. Prendergast1,2,3, Elizabeth M. Jaffee4
1Lankenau Institute for Medical Research, Wynnewood, PA USA
2Department of Pathology, Anatomy & Cell Biology
3Kimmel Cancer Center, Jefferson Medical School, Thomas Jefferson University,
Philadelphia, PA USA
4The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department
of Oncology, The Johns Hopkins University, Baltimore, MD USA
I. SUMMARY
Immunologicalthoughtisexertingagrowingeffectincancerresearch,correctingadivorcethat
occurred in the mainstream of the field decades ago as cancer genetics began to emerge as
adominantmovement.Duringthepastdecade,anewgeneralconsensushasemergedamong
all cancer researchers that inflammation and immune escape play crucial causal roles in the
developmentandprogressionofmalignancy.Thisconsensusisnowdrivinganewsynthesisof
1
thoughtwithgreatimplicationsforcancertreatmentsofthefuture.Inthisbook,weintroduce
new concepts and practices that will dramatically affect oncology by adding new immune
modalitiestopresentstandardsofcareinsurgery,radiotherapyandchemotherapy.Weaimin
particular to cross-fertilize ideas in the new area of immunochemotherapy, which strives to
develop new combinations of immunological and pharmacological agents as cancer thera-
peutics. Specifically, our goals are to (1) highlight novel principles of immune suppression in
cancer,whichrepresentthemajorsalientbreakthroughsinthefieldofcancerimmunologyin
the last decade, and to (2) discuss the latest thinking in how immunotherapeutic and
chemotherapeutic agents might be combined, not only to defeat mechanisms of tumoral
immune suppression but also to reprogram the inflammatory microenvironment of tumor
cells to enhance the long-term outcomes of clinical intervention. Many immune-based ther-
apies have focused on activating the immune system. However, it is now clear that these
therapiesareoftenthwartedbytheabilityofcancerstoerectbarricadesthatevadeorsuppress
the immune system. Mechanistic insights into these barricades have enormous medical
implications, not only to treat cancer but also many chronic infectious and age-associated
diseases where relieving pathogenic immune tolerance is a key challenge. In this book,
contributors with a wide diversity of perspectives and experience provide an introductory
overview to the immune system; how tumors evolve to evade the immune system; the nature
of various approaches used presently to treat cancer in the oncology clinic; and how these
approaches might be enhanced by inhibiting important mechanisms of tumoral immune
tolerance and suppression. The overarching aim of this treatise is to provide a conceptual
foundation to create a more effective all-out attack on cancer. In this chapter, we offer
ahistoricalperspectiveonthedevelopmentofimmunologicalthoughtincancer,adiscussion
of some of the fundamental challenges to be faced, and an overview of the chapters which
frame and address these challenges.
CancerImmunotherapy.http://dx.doi.org/10.1016/B978-0-12-394296-8.00001-4
Copyright(cid:1)2013ElsevierInc.Allrightsreserved.
Cancer Immunotherapy
II. HISTORICAL BACKGROUND
“Ican’t understandwhy peopleare frightened ofnew ideas.I’m frightened ofthe
oldones.”
eJohnCage(1912e1992)
Starting about 1980, researchinvestigations incancergenetics and cellbiology beganto
assume the prominence incancer researchthat they nowhold today.Hatched initiallyfrom
studiesofanimaltumorviruses,thefieldofcancergeneticshascontributedsignificantlytoour
understandingofthebiologicpathwaysinvolvedintumorinitiationandprogression,andhas
identified specific targets for therapeutic intervention. Withthe discoveryof cellularonco-
genes,theonceradicalideathatcancerwasadiseaseofnormalcellulargenesgonewrongnot
onlycameto be established asthe dominant idea inthe field but also to stronglyinfluence
how to developnewdrugs totreatcancer,with the goal ofattacking the products ofthose
genes.Atthesametime,thesedevelopmentsoutpacedotherconceptsofcancerasasystemic
disease involving perturbations inthe immune system. Now,afterdecades of mutual skepti-
cism,ahistorically importantconsensus amongcancer researchers is emergingabout the
causalityof chronicinflammation and altered immunity in driving malignant development
andprogression.Ironically,thissynthesisishavingtheeffectofmakingthe“new”geneticideas
ofthe past twodecadesabout cancer seem somewhat dated: in particular, it is becoming
apparentthat the tumorcell-centricfocuschampioned bycancer genetics is unlikelytogive
afull understanding of clinical disease, withoutknowingabout the systemicand localized
tissueconditionsthatsurroundandcontrolthegrowthandactivityofthetumorcell.Perhaps
contributingtosomeconsternationabouttheconceptualweightofthe“new”ideas,fewofthe
molecular therapeutics developed from them have had much majorclinical impact (the
(cid:3)
Bcr-Abl kinase inhibitor Gleevec stillperhapsthe most notable successamong present
2 molecular cancertherapeutics).
Amongtheearliestpathohistologicaldescriptionsofcancer,Virchowinthe1800sfirstnoted
thesurfeitofinflammatorycellsinmanytumors.Fromthisroot,tumorimmunologistshave
formanyyearsstruggledtofullyunderstandthepreciserelationshipsbetweeninflammation,
immunity, and cancer, and to develop principles thatcan robustlyimpact the diagnosis,
prognosis,and treatmentof cancer.Withthe emergence of cancer geneticsand tumor cell-
centricconceptsofdiseaseasmajorconceptualdriversinthelate20thcentury,rolesidentified
fortumor stromalcells and immunity in cancer became marginalizedor simply ignored by
manyinvestigators.Indeed,oldskepticismsaboutwhetherimmunitywasimportantornotin
cancer have persisted until quite recently,as can be illustrated bythe omissions of immune
escapeandinflammationascriticaltraitsofcancerininfluentialreviewsasrecentlyastheturn
ofthe newcentury [1]. However,since 2000perspectivesin the field haveonce again
undergonearadicalshift, with manycancer researchers nowfocusing intenselyon how
tumorigenesis and tumor dormancyversusprogression are shaped bythe stromalmicroen-
vironment, inflammation, and alterationsin the immunesystem. Indeed, arecent update to
theprominentreviewcitedaboverecognizedtheconceptualmovementinthisrapidlymoving
areaof the field, includinginflammation and immune escape as criticaltraits of cancer [2].
Therestorationofimmunologicalthoughtinthemainstreamofcancerresearchisproceeding
rapidly,creatingahistoricallyimportantsynthesisthatisseedingradicallynewapproachesof
immunochemotherapyand radioimmunotherapy[3]. Overthe past 25 years, as aresult of
historical and scientific divisions, there havebeen limited communication,understanding,
and collaboration between tumor immunologists,molecular geneticists,and cellbiologists
workinginthefield.Ononehand,thissituationhasbeenexaggeratedbywhatnowseemslike
anoverly narrowfocus of geneticists and cell biologists on tumorcell-centric concepts of
cancer,whichcontinues topersist tosome degree.On the other hand, immunologists have
struggled to establish aclearunderstanding of how inflammation and immune cells can
CHAPTER 1
Introduction
contributetopromotingorcontrollingcancer.Biasesrootedtosomeextentinoldcontroversies
thathavebeentransmittedtoyoungerscientistsenteringeachfieldhavefurtherlimited
communicationandinteractionbetweenthetwocamps.Happily,inrecentyearsmanyofthese
oldissueshavebeenputtorest,byexperimentsinmoderntransgenicanimalmodelsystemsand
bycarefullycontrolledclinicalobservations,suchthatthekeypathophysiologicalfoundations
ofinflammationandimmunedysfunctionincancerarenowfirmlyestablished[4].
Contributingtothenewperspective,thereisawiderappreciationofboththecriticalroleofthe
tumormicroenvironmentinmalignantdevelopmentandthepowerofimmunesuppression
mechanismsinlicensingcancercellproliferation,survival,andmetastasis.Intermsof
immunotherapeuticresponses,itseemsincreasinglyclearthatinorderto“pushonthegas”
ofimmuneactivation,itwillbenecessaryto“getoffthebrakes”ofimmunesuppressiondan
ideathatcancergeneticistsmayrecognizeasanalogoustotheconceptintheirfieldthat
oncogenescandriveneoplasticcellproliferationonlywhentheblockadesimposedby
tumorsuppressorgenesarerelieved.
III. THE CHALLENGE OF CANCER
Clearly,thegoalof cancer therapyis tokillresidual tumorthat cannot be excisedsurgically.
However, the inherent nature ofthe cancercelllimits the full effectivenessof therapies that
havebeendeveloped, or thatarguablycan be developed. Being ofhost origin, cancer cells
share featuresofthe hostthatmakeeffectivetreatmentdifficult, due toside effectsthat limit
the therapeutic window. Moreover, the plastic natureof tumors makesthemremarkably
resilientin rebounding from clinical regimens ofradiotherapyand chemotherapythat are
traditionally used.Forexample, evenwhenthe vastmajorityof cancer cells are killed by
acytotoxic chemotherapeutic drug, asmall numberof residual cells that are resistantto the
agentcan be sufficientto seed the regrowthof atumor. Makingmatters worse,the regrown
3
tumormayno longer respond to the previouslysuccessful therapy,due tothe capacityof
tumorcellstoevolveresistanceunderselectivepressuresappliedbycytotoxicagents.Indeed,
theconceptofselectionisintegraltounderstandingthisdisease:developmentandprogression
in cancer is drivenbythe selectionof cells that surviveconditions thatare normally lethal.
Resistanceto anynormally lethal pressurecan be selectedbyevolution inacancercell
population becauseof the genetic plasticity, an important characteristic of cancer cells.As
demonstrated in the treatmentof other diseases caused byahighly mutableentity, e.g., HIV,
successful targeting oftumorcells mayrequire theapplication of multipleagents thattarget
differentsurvivalmechanisms.However,comparedtoHIV,thegeneticspaceavailableforthe
evolutionofacancercellisfarlarger,duetothefargreatersizeofthecancercellgenome.Thus,
effectiveeradication of tumors has proven dand maycontinue to proveto bedquitechal-
lenging,evenusing multipleagents incombination, becauseof the diversityofoptions that
the cancer genome can realize to evolvemechanisms of survivalin response tomultiple
selection pressures these agents apply.Our best chance is toidentifyas manyofthese mech-
anisms as possible, and to discoverapproaches that synergizetoinhibit these many
mechanisms.
Twogeneralsolutionstothisdismalsituationmaybetoredirectthefocusofattackfromthe
tumorcell itselfto the environmentthatsustains its growthand survivalor to engage the
immunesystem inways thatallowsit toeradicate tumor cells like aninfection. The former
strategyisessentiallypassiveinnatureinsofarascancercellsarekilledbyanindirectroute.For
example, bydepriving tumors of ablood supplyanti-angiogenic therapies can indirectly kill
cancercells.Resistance tosuch therapies should be difficultto evolve, as the argument goes,
because stromal cells in the tumor environmentare not genetically plastic. However,due to
their passivenature such therapiesare still proneto circumvention throughtumorcell
evolution (e.g.,vascularmimicryin the case ofanti-angiogenesis therapies [5]).In contrast,
activestrategiestoengageor“awaken”activeimmunityinthecancerpatienthasmanyappeals,
Cancer Immunotherapy
the chief of which is its capability to “dodge and weave” with tumor heterogeneity,the
inherent outcomeof the responseof tumor cells toselection pressures. In this regard, the
immunesystemmaybeparticularlywellsuitedtoclearthesmallnumbersofresidualtumor
cells,particular dormant cells or cancerstem cells,thatmaybe poorlyeradicated byradio-
therapyand chemotherapyand whichcould help lengthen remission periods. Indeed, even
treatmentsthatdidnotcurebutratherconvertedcancertoalong-termsubclinicalcondition,
byanalogytoHIV infections,wouldrepresenta resounding success.Therefore, the key
questionbecomeshowatumorcanoutrunanactivatedimmunesystem,giventhatprecisely
thiseventhasoccurredduringtumorigenesis,sothatthebalancemightbetippedbackinfavor
ofthe immunesystem.
IV. PARTS OF THE BOOK
The second edition of this book providesasignificant expansionupon the first edition,
reflecting rapid developments incancer immunologyand the new field ofimmunochemo-
therapy. The book encompasses twogeneral parts,which are subdividedinto three sections
each.Thefirstpartofthebookintroduceskeyconcepts,withSectionsIeIIItointroducebasic
principlesofimmunology,cancerimmunobiologyandcancertherapeutics.Thesecondpartof
the book introducesstrategiesto stimulateor heighten (andmeasure)immunotherapeutic
responses, with Sections IVeVI devotedto passiveand activeimmunotherapy, potential
improvements with existing tools,and emergingstrategies to target mechanisms of tumoral
immunosuppressionthatarebeingdiscoveredalongwithnovelexperimentaltools todoso.
Section Iintroduces basic principles in immunology for the large numberofindividuals
workingor interested incancerresearchwhoremainrelativelyunschooled inthis discipline.
Thissectiondoesnotdelveintoeverytopicbutoffersrudimentsrelevanttokeydirectionsin
the field. Fundamental components of the immune system are introducedin Chapter2
4
spanningboth innate and adaptiveimmunity.The followingchapters focus more deeplyon
theadaptiveimmunesystem,whichtumorsmustultimatelyerectpowerfulbarricadesagainst,
withChapter 3 addressing Bcells and antibodiesand Chapter4 addressing Tcells and cyto-
kines.Chapter 5 introducesantigen processing and presentation to the adaptiveimmune
system as carried out bydendritic cells,aclass ofmyeloid cells specificallydedicated toanti-
gen presentation. Thischapteraddresses an importantarea ofcancer immunobiology and
therapyatpresent,insofarasitencompassesthefirstactiveimmunotherapytobeapprovedin
the U.S. for cancer treatment. Chapter 6 introducesmucosalimmunity,an areaof rapidly
expandinginfluencedueinparttoagrowingappreciationofhowtheaerodigestivetractsnot
onlyshapetolerancetoenvironmentalantigensbutalsotohowthegutmicrobiomeprograms
immunityoverall[6].
Section IImovesspecifically into thegeneral principles ofcancerimmunobiology, aseminal
areathatisrenewingitshistoricalimpactoncancerresearchafterthedivorceofimmunology
fromthe mainstream of the field withthe molecular genetics revolution ofthe 1980s.Key
chaptershighlightthe significance of tumorimmunoediting and immune suppression
mechanismsinprogression.Twofundamentalideasherearethatsubclinical(occult)cancers
mayarise commonlyduring aging and thatclinical cancer mayrepresent only those rare
lesions thathaveachieved immune escape.In cancer research, modelsof oncogenesis have
exertedthemostinfluenceoncancercell-centricconcepts,whereasmodelsofimmunoediting
haveassumedamajorinfluenceoncancermicroenvironmentconcepts.Chapter7introduces
cancer immunoediting as afundamental process with three parts,namelyimmuno-
surveillance, immune equilibriumand immune escape, which lead respectivelytocontrol,
stasis,oroutgrowthofamalignancy.Immunoeditingstartswiththeimmunerecognitionand
destructionof cells thathaveacquired genetic and epigenetic alterations characteristic of
tumor cells,but at the same time, the selectivepressureproducedbyimmunoediting drives
tumor evolution and progression. In this process,the cell-intrinsic traits ofcancer
CHAPTER 1
Introduction
(immortalization, growthderegulation, apoptotic resistance, and tumor suppressor inactiva-
tion)leadtothedevelopmentofsubclinicaloroccultlesionsthatarenotclinicallyimportant
untilcell-extrinsic traits (invasion, angiogenesis,metastasis,and immune escape)have been
achieved.Thecomplexrolesforinflammatorycellsandalteredimmunityinthedevelopment
of cell-extrinsictraits represent anincreasingly important areafor investigation. Chapter 8
discusseskeyaspectsofimmunosurveillance,includingtheproductionof“dangersignals”and
the generation ofinnateand adaptiveimmune responses totumorcells.Chapter9discusses
immune“sculpting”processesthatoccurinthetumorasaresultoftheevolutionofthebattle
between immune cells and tumor cells,focusing on key roles playedin the inflammatory
tumormicroenvironmentbynaturalkillercells(NKcells).Chapters10and11discussimmune
escape. Atimely focus on rapid developments in studies of Th17 helper cell-based immuno-
suppression are addressed in Chapter 10, with abroader overviewof immunosuppressive
networkspresented inChapter 11. With the evolution of immunosuppressivenetworksby
tumors,immunoediting eventuallyculminates inan escape fromimmune control, initially
locally topermittumorgrowthbut ultimately toinvasiveand metastatic states that can
challenge or defeatclinical management.
SectionIIIprovidesanintroductoryoverviewtocancertherapeuticsandstrategiesof
development,includingperspectivesonpharmacologyandsafetyassessment,cancervaccines
and immunoguidingtactics.Chapter12 introducescytotoxicchemotherapeutics,which
continuetoprovidethemajorpartofthearmamentariumemployedbymedicaloncologists.
Chapter13 offersanoverviewofcancerpharmacologyandsafetyassessmentforboth
“classical”typesofcytotoxicdrugsas wellasmodernmoleculartargetedtherapeutics,where
thecentralgoalislearningwhether“hittingthetarget”inthetumorcell(pharmacodynamics)
canbeachievedinarelativelysafeandeffectivemanner.Strategiesforpassiveimmunotherapy
withmonoclonalantibodiesarereviewedinChapter14.Althoughittooktwodecadesto
fullymature,thisareaofimmunotherapyhasachieved considerablesuccessyetmayseestill
5
greaterinfluenceincancertreatment, particularlyintargetingT-cellnegativeco-regulatory
(cid:3)
pathwayswiththerecentU.S.approvalofanti-CTLA4therapy(ipilumimaborYervoy ),which
isthefocusofalaterchapter.Chapter15 introduces strategiesforactiveimmunotherapy
withafocuson cancervaccines.Whilepursuedformanyyearstogenerallyfrustratingends,
cancervaccinestrategiesappearpoisedtobreakthroughtosignificantclinicalimpactswiththe
combinationoftargetedstrategiesthatcanattenuatetumoralimmunosuppression(as
introducedinSectionsVandVI).Chapter16introducesconceptsinimmunoguidingdthatis,
thedevelopmentoftacticstoguidetheuseofimmunotherapybasedonchangesinthe
qualityorquantityofimmunemetricsintreatedsubjects.Thisareaencompassesthegeneral
areaofimmunopharmacology,whichwillbecriticalforthesuccessfuldevelopmentof
tailoredorpersonalizedtreatmentsindifferentdiseasesettingsandpatients.
Section IVopens the second half ofthe book,whichaddresseshowto improve survival
outcomesusing immunotherapeutic strategies.Thissection offers examples of howdifferent
passiveoractiveimmune strategiesare yielding knowledgeinto howtoharnesstheimmune
systemtoattacktumors,withafocusoncellulartherapies,vaccinesandimmunecheckpoint
antibodies.These approachesmayall benefitconsiderablyfrom combinations with one or
morestrategiesforreversingtumoralimmunesuppressionintroducedinthelastsectionofthe
book,withthepotentialtoreduceorevenrelieveneedsfortraditionalchemotherapy,which
mightultimatelybeunseatedasastandardofcare.InChapter17,thefieldofadoptiveT-cell
therapyis discussed, focusingon howefforts in engineering T-cellreceptors have greatly
leveragedtherapeutic impact.Chapters18and19offer lessonsgainedfromstudyofthefirst
activeand passiveimmunotherapiestobe approved bythe U.S. FDAfor patient treatment,
(cid:3)
namely,the autologous dendriticcell vaccinesipuleucel-T (Provenge ) and the anti-CTLA4
(cid:3)
antibody ipilumimab (Yervoy ).In seekingto promote more effectivetumorantigen
(cid:3)
presentation,Provenge offersthefirstofmanystrategiesthatwillnodoubtbedevelopedto
(cid:3)
improve the activityofdendriticcells in cancer patients.Incontrast, Yervoy offers the first
Cancer Immunotherapy
ofmanystrategies thatwillno doubt be developed to block negativecoregulatorysignals
(immunecheckpointsignals)whichstanchimmuneactivationbytumorantigens.Chapter20
describes lessons gained from development of one ofthe morethoroughlystudiedtumor
(cid:3)
antigenvaccines,PSA-TRICOM,whichlikeProvenge wasdevelopedforprostatecancer.Asan
illustrationofthedevelopmentofthecancervaccinefield,thisprojecthasyieldedsignificant
information over the years.Lastly, Chapter21 addresses adjuvant strategiesfor vaccines. The
introductionofappropriateadjuvantstovaccinationsagainstinfectiousdiseasesinthe1950s
hadanenormousimpactonefficacy,andsimilarfactorsmayalsoaffecttheimpactofcancer
vaccinesdespiteinterestin their use for treatmentas wellasprophylaxis.
Section Vaddresses howtoimprove clinical responses using combinations ofagents that
constitute immunochemotherapy(seeFigure 1.1).Cancerpharmacologyand cancer immu-
nologyareeachverywell-developedfields,buteffortstoinvestigatecombinatorialregimensat
this interfaceat either the preclinicalor clinical levelremain littledeveloped. Conceptual
barriersbetweenfieldsthatwerecreatedbyhistoricaldevelopmentsarenowfading[3],butthe
lack ofcross-communicationand cross-fertilization still represent impediments to the devel-
opmentofimmunochemotherapyevenwithexistingtools.Thissectionofthebookhighlights
areaswheretherearesomestrongargumentsformultidisciplinaryinvestigationsandclinical
trials.Chapter 22 examines the use of small molecule inhibitors of histone deacetylase
(HDAC) as anillustration of howepigenetic modification maybe importantinthe immune
microenvironmentofcancer,aswellascancercellsthemselves(whereepigeneticstudieshave
6
FIGURE 1.1
Immunochemotherapyofthefuture.Thenewsynthesisofimmunologicalthoughtwiththemainstreamofcancerresearch
isstimulatingthecreationandevaluationofnewcombinationsoftherapiesthatcanstimulatetheimmunesystem,
relievetheimmuneblockadeserectedbytumorcells,andtriggerpro-immunogenictumorcelldeaths.Immuneblockades
erectedbytumorsareassociatedwithalteredinflammatory“flavors”oftheirmicroenvironment,switchingitscharacterfrom
antagonistictosupportivefortumoroutgrowth.Thus,agentsthatcanreprogramtheinflammatorymicroenvironmentor
blocktolerancedthesemaybegeneticallysynonymous[8]dmayfurtherleveragetheefficacyofimmunochemotherapies
thatarecomprisedofexistingstrategiestostimulateimmunityandkillcancercells.
CHAPTER 1
Introduction
focusedtodate).Chapter23discussestoolstoprofileimmunotherapeuticresistanceincluding
such epigenetic changesthat affect gene expression. Chapter 24 discusseshowtraditional
cytotoxicchemotherapynotonlystimulatesimmuneactivitybutindoingsoimprovesefficacy.
Whilesomeofthisinformationhasexistedforsometime,ithasnotbeenwidelyappreciated,
and only recently have mechanismsemerged thatcan begintoexplain the basis for immu-
nostimulatoryeffectsoftraditionalchemotherapy.Inclosingthissection,Chapter25discusses
howharnessingtheseeffectsmayrepresentagoldenopportunityincombinationswithactive
immunotherapy. Such ideas havebeen heterodox until recently, with the bias thatchemo-
therapycouldonlydamage the immune system and therebyhinderthe desired effects of
immunotherapy.Itisnowbecoming clearthis widelyheldviewisincorrect.Indeed,withan
emerging appreciationofhowtraditionalcytotoxic chemotherapies engage the immune
systemdand perhapsmust engageitdit maybe possible to define immunochemotherapy
combinations thatimprove durableclinical responses and long-term survival inpatients.
Section VIintroduces the exciting and rapidly growingknowledgebaseconcerning the
molecular nature of immunosuppressivebarriers erectedbytumors.Targetingthose barriers
nowbecomespossiblewiththeseadvancesasrationalstrategiestodegradeordefeatimmune
escape. One common thread inthis chapter is the presentation of different perspectiveson
myeloid cells derivedfrom the innate immunesystem thathelp shape the inflammatory
state(s)thatsupportinvasivecancerandmetastaticprogression.Tumorstromaincludealarge
numberof these cells.Indeed, emerging work tends to supportthe concept[8] that mecha-
nismsof immuneescape overlap genetically withmechanisms of cancer-associated inflam-
mation, perhapsprincipally involving myeloidcells,such thatcorrectiveapproaches to
immuneescape might be viewedas synonymous with inflammatory reprogrammingof the
tumormicroenvironment.
Section VIdiscusses avarietyof cellular and molecularprinciples along with tractable thera-
peuticapproachesforclinicalevaluation.Chapter26discussestheareaofJAK/STATsignaling, 7
whereone of the first clinicallyapproved inhibitors for exploration in theoncologyclinic
has emerged, with afocus on myeloid cells.Chapters 27 and 28 focus on twomyeloid cell
subsets of great interest,the tumor-associated macrophages (TAM) and the myeloid-derived
suppressor cells (MDSC),each of which contribute stronglyto procancerous inflammatory
programmingin the tissue microenvironmentof cancer cells.Chapter 29 introducesHyper-
Acutevaccines,aprovocativenewclass ofnonautologouswhole tumor cell vaccinesengi-
neeredtoharnessthehyperacutexenotransplantationrejectionresponseasageneralstrategy
to reprogram inflammation in the context oftumorantigen presentation. Earlyclinical trials
suggest the HyperAcuteapproach maybroadlydegrade suppression mechanisms against
tumorantigensin amanner associated with eosinophil recruitment. The remainingchapters
shift from cellular tomolecular principles of immunosuppression. Chapter 30 discussesthe
explodingworkontumor-associatedexosomes,comprisedofsmallvesiclessecretedfromcells
whichconveyhormone-like messages intissues (proteins,microRNAs and other compo-
nents).Exosomes maytolerize dendritic cells to antigensand mediate criticalinflammatory
and immune regulatorysignals inthe tumormicroenvironment, with majorprognostic and
therapeuticimport.Chapters31e34focusonmolecularprinciplesofimmunomodulationby
galectins, indoleamine 2,3-dioxygenase (IDO), arginase and nitric oxide (NOS). This area
encompasses the fascinatingnew field of tumor immunometabolism. Together, there is
growingevidencethatthesecellularandmolecularactorsmaybebroadlyinvolvedincancer
immunosuppression,promptinggreatinterestinclinicalstudyofinhibitorsthatcandegrade
the metabolic barricades theyerect tohelp tumors evadeimmunecontrol. Strategiesfor
therapeuticinactivationofthesemechanisms,whicharenowlargelywelljustifiedfromwork
in preclinicalmodels,are movingforwardpresentlyin earlyclinical trials.
Together,theareasdiscussedinthissectionofthebookprovideanoverviewofdifferenttypes
of immunotherapeutic approaches being taken to capturedifferentelements ofthe
Cancer Immunotherapy
immune system to more effectivelyattack and eradicate tumor cells.In the present culture,
cancer immunologiststendto be oriented to biological therapiesand tohavelimited
knowledge ofcancerpharmacologyor genetics.Conversely,cancergeneticists and pharma-
cologists tend tobe oriented toward small molecule therapiesand tohavelimited
understandingofcancerimmunologyorimmune-basedtherapies(otherthanperhapspassive
immune therapies,e.g., antibodies). Itis hoped thatthis book can revealwhyinteractions
betweenthese twostill relativelydisparate groups will be both intellectuallyand clinically
rewarding astheexcitingnew field of immunochemotherapyunfolds this decade. With the
endof along separation between cancer biologistsand cancer immunologists [7], this new
conceptualsynthesisincancerresearchmayrepresenttheopeningstageofanall-outwaron
cancer withbetterhopes of obliterating this terrible disease.
ACKNOWLEDGMENTS
Workin the authors’laboratories has been supported byNIH grants CA109542,CA159337
and CA159315, New Link GeneticsCorporation, Sharpe-StrumiaResearch Foundation,
LankenauHospitalFoundationandtheMainLineHealthSystem(G.C.P.)andbyNIHgrants
R01CA122081, P50CA062924, and P50CA088843(E.M.J.).Dr. Jaffee is the first recipient of
the Dana and Albert “Cubby”BroccoliProfessorship inOncologyand the co-director of the
SkipViraghPancreaticCancerCenteratJohnsHopkinsUniversity.G.C.P.declarescompeting
interests as ascientificadvisor, grantrecipient and stockholder inNewLink Genetics Corpo-
ration,whichisdevelopingHyperAcutevaccinesandwhichhaslicensedpatentedtechnology
fromthe author’sinstitutionto developsmallmolecule inhibitorsof IDO and the IDO
pathwayfor the treatment ofcancerand other diseases.E.M.J. declarescompetinginterests
based upon licensingofpatented vaccines from theauthor’sinstitutionto BioSantePhar-
maceuticalsand AduroBioTech Inc. The inventions fromboth authors have the potentialto
generatefuture royalties.
8
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[3] Prendergast.Immunologicalthoughtinthemainstreamofcancerresearch:pastdivorce,recentremarriageand
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[4] DunnGP,OldLJ,SchreiberRD.ThethreeEsofcancerimmunoediting.AnnRevImmunol2004;22:329e60.
[5] FolbergR,HendrixMJ,ManiotisAJ.Vasculogenicmimicryandtumorangiogenesis.AmJPathol
2000;156:361e81.
[6] ChoI,BlaserMJ.Thehumanmicrobiome:attheinterfaceofhealthanddisease.NatRevGenet
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IDOpathway.AmJPathol2010;176:2082e7.
2
CHAPTER
Components of the
Immune System
Amanda Norvell
Department of Biology, The College of New Jersey, Ewing NJ USA
I. OVERVIEW
Theimmunesystem,whichiscomprisedofadiversecollectionofcells,moleculesandorgans,
doesanastonishingjobofprotectingindividualsfromdangersasvariedasforeignpathogens
and cancerouscells.When functioningappropriately,the workof the immune system goes
unnoticed but in cases ofimmune dysfunction severe consequencesresult inthe formof
autoimmunity orimmunodeficiency.Orchestratingappropriate and protectiveimmune
responsesrequiresahighdegreeofcoordinationandcommunicationbetweenmultiplecells.
This chapterwill present ageneral overviewof the human immune system, describingthe
generalorganization ofthe immune system and introducing the major celltypes and
responses,thusprovidingaconceptualframeworkuponwhichthefuturechapterswillbuild. 11
Inthesimplestterms,theimmunesystemidentifiesandeliminatesdangerouselements.Todo
sorequirestwocriticalactivities:recognition,identificationoftheharmfulagent,the“antigen,”
byspecific receptors expressedon the surfaceof immunesystem cells,followed byeffector
responses, the cellular behaviorsthat confer protection. A protective immune response that
eliminatesor neutralizes theantigeninvolvesthesynchronized activityofmultiple cell types
and avarietyofcellularresponses.Communication between the cells occursthroughboth
cellecellcontact-mediatedsignaling,aswellasthroughchemicalsignalsthataresecretedfrom
onecellandreceivedbyothers.Manyofthecells,suchasmacrophagesanddendriticcells,that
participate in an immune responsedo sobyrecognizing foreigncells and then responding
throughavarietyofactivitiesthatbothpromotetheirdestructionorclearanceandhelptoalert
othercells ofthe immunesystem to the danger.Other specialized cells,called lymphocytes,
circulateand patrol the body lookingfor foreignsubstances.Each lymphocyte is capable of
recognizing onlyasingle antigen, soprotection for the organismis achievedbyhaving
averitablearmyof diverselymphocytes circulating at anygiventime.Once aparticular
lymphocyteencountersanantigenitrespondsbyproliferatinganddifferentiatingtoformcells
withspecificfunctionalactivities,suchascytotoxic Tlymphocytes(CTLs)thatarecapableof
directkilling of target cells,and long-lived memorycells that remain in the body, poised to
respond to the antigen if it is encounteredagain.While the molecular events thatoccurin
individualcellsarecriticalandhavebeenthesubjectofextensiveinvestigation,thedetailsof
howmanycellsandcellularresponsesarecoordinatedtoofferrobustprotectionagainstvaried
dangers,or howtheimmune response is deregulated incasesof autoimmunityor immuno-
deficiency, are areas of activeresearch.
Thestudyoftheimmunesystemgrewfromconcernabouthumanhealthandtheunderstanding
thatmicrobescancausedisease.Immunologyasafieldofstudyemergedasscientistsofthe
19thcentury,suchasLouisPasteurandRobertKoch,beganworkonthegermtheoryofinfection.
CancerImmunotherapy.http://dx.doi.org/10.1016/B978-0-12-394296-8.00002-6
Copyright(cid:1)2013ElsevierInc.Allrightsreserved.
SECTION 1
Principles of Basic Immunology
Onceestablishingthatmicrobescancauseillness,thenextnaturalstepwastounderstand
howtoprotectpeoplefrominfectiousdiseases.Thehistoricobservation,datingasfarback
asancientGreece,thatthosethathadbeensickandrecoveredwerenaturallyresistantto
futureillnessledtothesystematicstudyofhowexposuretomicrobesleadstoprotectionfrom
disease.Thischaracteristic,calledmemory,isoneofthemostremarkablefeaturesofthe
immunesystem.Notonlydoestheimmunesystemrememberwhatforeignagentsithasseen,
butuponsubsequentencounterwiththesameagent,the“secondaryimmuneresponse”is
greatlyenhanced;itoccursmorerapidlyandwithmuchmoreeffectiveforce.Immunememory
isthebasisforvaccinationandcurrenteffortsarefocusedonunderstandinghowtopromote
protective,long-livedimmunitytoparticularpathogensortocancers.
II. PRINCIPAL TISSUES AND ORGANS
The immune system is formed byavariedcollection ofinterconnected cells and tissues
distributedthroughoutthe body.The majorcell types that comprise the immune system are
describedbrieflybelow,butforthemostpartmanyofthesecellsarecirculatoryormigratory.
The lymphoid organs,includingthe primarylymphoid organs(bone marrowand thymus)
and the secondarylymphoid organs (includingregional lymphnodes and spleen), are
connected toone anotherthrough twoseparate circulatorysystems,theblood system and
the lymphatic system. The primarylymphoid organsare the sites of white blood cell
production and differentiation, whilethe secondarylymphoid organs and the circulatory
systemsoutsideoftheprimarylymphoidorgansarecollectivelyreferredtoasthe“periphery.”
The lymph nodes and spleen serveto filter and trap foreign moleculesand cells that are
deliveredfrom the tissues via the lymph fluid or the blood.In addition, the secondary
lymphoid organsalso providean organized tissue inwhich the white blood cells can both
encounterforeignantigenmoleculesandcanphysicallyinteractwithotherwhitebloodcells
12 toinitiate anappropriateimmune response. Generally,all secondarylymphoid organs have
asimilar overallstructure, withmost havingakidney-bean shapethat is covered byathick
capsule [1]. Within the lymphoid organs,subdomains such as the cortex,paracortex and
medullacanalsobedistinguishedmorphologicallybecausedifferentpopulationsofcellsare
enrichedinspecificregionsoftheorgans.Bloodandlymphfluidaredeliveredanddrainedto
and from the lymphoid organs bythe afferentand efferent vesselsrespectively. Additionally,
highlyspecialized subregions of the spleen called germinal centers,which are required for
the formation ofmemory Bcells,formduringthe courseof animmuneresponse [2,3].
III. CELLS OF THE IMMUNE SYSTEM
The majorcells ofthe immune system are an assortmentof blood cells that can be grouped
into three generalcategories,the lymphocytes, includingTcells,Bcells and Natural Killer
(NKcells);themyeloidcells,whichincludetheantigenpresentingcells,themacrophages,and
dendriticcells (DCs); and finallythe granulocytic cells, such as neutrophils, basophils,and
eosinophils.Forthe most part all of these cells are derivedfrom acommon stem cell
(Figure2.1).Inadulthumanbloodcellproduction,aprocesscalledhematopoesistakesplace
inthe bone marrow. This microenvironment, which contains multiplesupportcells inthe
formof epithelialcells and stromal cells,promotes the division and differentiation of devel-
oping blood cells.Throughout humanontogenythesiteof hematopoesis shifts: during fetal
stages blood cells are initiallyderived in the fetal liver, then theirdevelopment shifts to the
neonatalspleen,andfinallyaroundbirthhematopoesismovestothebonemarrow.Allblood
cells,includingred blood cells and the white blood cells of the immune system,develop
fromhematopoietic stem cells that divide to both self-renewand toproduce pluripotent
progenitorcells[4].Theseprogenitorsdifferentiatedownoneoftwomajorpathways,aseither
lymphoidcells,whichfurtherdevelopintocellsoftheB-celllineage,T-celllineageorNK-cell
lineage, or into granulocyte/monocyte progenitors thatcan differentiate into specialized
