Cancer immunology

NOTE

1. CANCER
IMMUNOLOGY
Presented by: Zahabiya Dhankot
(M.Sc. Biochemistry)

2. TOPICS INCLUDED
Thecancersoftheimmunesystem.
Howthetumorgrowthisenhancedinthebody
Tumorantigens
Inductionofimmuneresponseandparticipationof
variouscells
Eliminationoftumorandcancerouscells.
Cancerimmunotherapy

3. INTRODUCTION
Inthebodythenumberofcellsismaintainedafter
maturationbycreatingabalancebetweenthe
numberofcellsproliferatedandthecells
undergoingdeath.Ifthiscontrolmechanismis
disturbedwithinthebodythenuncontrolledcell
multiplicationoccurswhichleadstothetumorous
orcancerousgrowth.
Immunesystemisthedefensemechanismofthe
bodyagainstanyforeignparticles.

4. TUMORS OF IMMUNE SYSTEM

5. Lymphomaproliferateassolidtumorswithina
lymphoidtissuesuchasbonemarrow,lymphnodes
andthymus.
Leukemiacandevelopassinglecellandare
detectedbyincreaseincellnumberinbloodand
lymph.
Itcanbedevelopedinmyeloidorlymphoid
lineages.
Historically,itisclassifiedonthebasisofclinical
progressionofdisease.

6. Theyare
Acuteleukemia
Theyappearsuddenlyandrapidlyprogress
Theyhavegoodprognosisandpermanent
remissioncanoftenbeachieved.
Tendtoariseinlessmaturecells.
ItincludesAcuteLymphocyticLeukemia(ALL)
andAcuteMyelogenousLeukemia(AML).

7. Chronicleukemia
Theyarelessaggressiveanddevelopslowlyand
mild,barelysymptomaticdisease.
Theyariseinmaturecells.
These includeschroniclymphocytic
leukemia(CLL)andchronicmyelogenic
leukaemia(CML).
Theyarefoundmostlyinadults.

8. ENHANCEMENT OF TUMORS
BYANTITUMORANTIBODIES
Theimmunizationofthetumoritselfsometimes
didnotprotectagainsttumorgrowth,butactually
enhancethegrowthoftumor.
Heretheantitumorantibodiesitselfactasa
blockingfactor.
BYANTIGENICMODULATION
Certaintumorspecificantigensareobservedto
disappearfromthesurfaceoftumorcellsinthe
presenceofserumantibodyandthentoreappear

9. aftertheantibodyisnolongerpresent.This
phenomenoniscalledantigenicmodulation.
POOREXPRESSION OFCLASS-IMHC
MOLECULES
CD8+CTLsrecognizeantigensonlyassociated
withclass-IMHCmolecules.
Anychangesinexpressionofclass-IMHC
moleculeswilldecreasetheCTLmediatedimmune
response.
Manytumorsshowsdecreaselevelofclass-IMHC
molecules.

10. Thedecreaseinitsexpressionisoftenaccompanied
byprogressivetumorgrowthandsotheabsenceof
MHCmoleculeontumorcellisgenerally
indicationofpoorprognosis.
REQUIREMENT OFSTIMULATORY AND
COSTIMULATORY SIGNALS
Activationsignal:-Itistriggeredbyrecognitionof
apeptideMHCmoleculecomplexbytheT-cell
receptor.

11. Co-stimulatorysignal:-Itistriggeredbythe
interactionofB7onantigenpresentingcellswith
CD28ontheT-cells.
BoththesesignalsareneededtoinduceIL-2
productionandproliferationofT-cells.

12. TUMOR ANTIGENS
Twotypesofantigenshavebeenidentifiedon
tumorcells:
1)TumorSpecificTransplantationAntigen(TSTA)
2)TumorAssociatedTransplantationAntigen(TATA)
TSTAareuniquetotumorcellsanddonotoccuron
normalcellsinthebody.
Thesearepresentedwithclass-IMHCmolecules,
includingacellmediatedresponsebytumor
specificCTLs.

13. TATAareuniquetotumorcells,theymaybea
proteinsthatareexpressedonnormalcellsduring
fetaldevelopmentwhentheimmunesystemis
immatureandunabletorespond.
Reactivationoftheembryonicgenesthatencode
theseproteinsintumorcellsresultintheir
expressionofthefullydifferentiatedtumorcells.
Itisnowclearthatthetumorantigensrecognizeby
humanTcellsfallintofourmajorcategories:

14. 1)Antigensencodedbygenesexclusivelyexpressed
bytumors.
2)Antigensencodedbyvariantformsofnormal
genesthathavebeenalteredbymutations.
3)Antigensnormallyexpressedatcertainstagesof
differentiationoronlybycertaindifferentiation
lineages.
4)Antigenswhichareoverexpressedinparticular
tumors.

15. Manytumorantigensarecellularproteinsthatgive
risetopeptidespresentedwithMHCmolecules.
Theseantigenshavebeenidentifiedbytheirability
toinducetheproliferationofantigenspecificCTLs
orhelperT-cells.

17. INDUCTION OF IMMUNE
RESPONSE BY TUMORS
Tumorantigenscaninducebothhumoralandcell-
mediatedimmuneresponsesresultinginthe
destructionoftumorcells.
Amongthesethecellmediatedimmuneresponse
playsamajorrole.
Manytumorshavebeenshowntoinducetumor
specificCTLsthatrecognizetumorantigens
presentedbyclass-IMHConthetumorcells.

18. ROLE OF NK CELLS
TherecognitionoftumorcellsisnotMHC
restricted.Therefore,theactivityofthesecellsdoes
notchangebytheexpressionofMHCmolecules.
FcreceptorpresentontheNKcellsbindsto
antibodycoatedtumorcellsleadingtoADCC.

19. ROLE OF MACROPHAGES
Macrophagesareobservedtoclusteraroundtumors
andtheirpresenceisoftencausetumorregression.
TheycarryoutthesamefunctionasNKcellswith
thehelpofFcreceptor.
Thesecellscarryouttheirantitumoractivityby
secretinglyticenzymes,reactiveN
2andO
2
intermediates,cytokinecalledTumorNecrosis
Factor(TNF-α)thathavepotentantitumoractivity.

20. ELIMINATION OF TUMOR CELLS
Over the past decade there has been notable
progress in the concept of cancer
immunosurveillance and immunoediting based on
(i) Protection against development of spontaneous and
chemically-induced tumors in animal systems.
(ii) Identification of targets for immune recognition of
human cancer.
Cancer immunosurveillance:-It is an important host
protection process that inhibits carcinogenesis and
maintains regular cellular homeostasis.

22. Immunoediting:-Itisaprocessbywhichapersonis
protectedfromcancergrowthandthedevelopmentof
tumourimmunogenicitybytheirimmunesystem.
Ithasthreemainphases:elimination,equilibriumand
escape.
Theeliminationphaseconsistsofthefollowingfour
phases:
Phase1::Thefirstphaseofeliminationinvolvesthe
initiationofantitumorimmuneresponse.Duringthis
phase,theinfiltratinglymphocytessuchasthenatural
killercellsandnaturalkillerTcellsarestimulatedto
produceIFN-ϒ.

23. Phase2::NewlysynthesisedIFN-gammainduces
tumordeath(toalimitedamount)aswellaspromotion
ofchemokines.Thesechemokinesplayanimportant
roleinpromotingtumordeathbyblockingthe
formationofnewbloodvessels.Tumorcelldebris
producedasaresultoftumordeathistheningestedby
dendriticcells,followedbythemigrationofthese
dendriticcellstothedraininglymphnodes.
Therecruitmentofmoreimmunecellsalsooccursand
ismediatedbythechemokinesproducedduringthe
inflammatoryprocess.
Phase3::Naturalkillercellsandmacrophages
transactivateoneanotherviathereciprocalproduction
ofIFN-gammaandIL-12.

24. Inthedraininglymphnodes,tumor-specificdendritic
cellstriggerthedifferentiationofTh1cellswhichin
turnfacilitatesthedevelopmentofCD8+Tcells.
Phase4::tumor-specificCD4+andCD8+Tcells
hometothetumorsiteandthecytotoxicT
lymphocytesthendestroytheantigen-bearingtumor
cellswhichremainatthesite.
EquilibriumandEscape
Tumorcellvariantswhichhavesurvivedthe
eliminationphaseentertheequilibriumphase.Inthis
phase,lymphocytesandIFN-gammaexertaselection
pressureontumorcellswhicharegeneticallyunstable
andrapidlymutating.

25. Tumorcellvariantswhichhaveacquiredresistance
toequilibriumthenentertheescapephase.Inthis
phase,tumorcellscontinuetogrowandexpandin
anuncontrolledmannerandmayeventuallyleadto
malignancies.

27. CANCER IMMUNOTHERAPY
ManipulationofCo-StimulatorySignalsCanEnhance
Immunity
Severalresearchgroupshavedemonstratedthattumor
immunitycanbeenhancedbyprovidingtheco-
stimulatorysignalnecessaryforactivationofCTL
precursors(CTL-Ps).
Ashumanmelanomaantigensaresharedbyanumber
ofdifferenthumantumors,itmightbepossibleto
generateapanelofB7-transfectedmelanomacelllines
thataretypedfortumor-antigenexpressionandfor
HLAexpression.Inthisapproach,thetumorantigen(s)
expressedbyapatient’stumorwouldbedetermined,
andthenthepatientwouldbevaccinatedwithan
irradiatedB7-transfectedcelllinethatexpressessimilar
tumorantigen(s).

28. EnhancementofAPCActivityCanModulateTumor
Immunity
Oneapproachthathasbeentriedistotransfecttumor
cellswiththegeneencodingGM-CSF.These
engineeredtumorcells,whenreinfusedintothepatient,
willsecreteGMCSF,enhancingthedifferentiationand
activationofhostantigen-presentingcells,especially
dendriticcells.
Anotherwaytoexpandthedendritic-cellpopulationis
toculturedendriticcellsfromperipheral-blood
progenitorcellsinthepresenceofGM-CSF,TNF-α,
andIL-4.Thesethreecytokinesinducethegeneration
oflargenumbersofdendriticcells.

29. Anumberofadjuvant,includingtheattenuated
strainsofMycobacteriumboviscalledbacillus
Calmette-Guerin(BCG)andCorynebacterium
parvuum,havebeenusedtoboosttumorimmunity.
CytokineTherapyCanAugmentImmune
ResponsestoTumors
cytokinesthathavebeenevaluatedincancer
immunotherapyareIFN-α,βandϒ;IL-1,IL-2,IL-
4,IL-5,andIL-12;GM-CSF;andTNF.Although
thesetrialshaveproducedoccasionalencouraging
results,manyobstaclesremaintothesuccessfuluse
ofthistypeofcancerimmunotherapy.

30. INTERFERONS
Largequantitiesofpurifiedrecombinant
preparationsoftheinterferon,IFN-α,IFN-β,and
IFN-ϒarenowavailable,eachofwhichhasshown
somepromiseinthetreatmentofhumancancer.
Allthreetypesofinterferonhavebeenshownto
increaseclassIMHCexpressionontumorcells;
IFN-ϒhasalsobeenshowntoincreaseclassII
MHCexpressiononmacrophages.

31. TUMORNECROSISFACTORS
Insomeinstances,thetumornecrosisfactorsTNF-α
andTNF-βhavebeenshowntoexhibitdirectantitumor
activity,killingsometumorcellsandreducingtherate
ofproliferationofotherswhilesparingnormalcells.
InthepresenceofTNF-αorTNF-β,atumor
undergoesvisiblehemorrhagicnecrosisandregression.
TNF-αhasalsobeenshowntoinhibittumor-induced
vascularisation(angiogenesis)bydamagingthe
vascularendothelialcellsinthevicinityofatumor,
therebydecreasingtheflowofbloodandoxygenthatis
necessaryforprogressivetumorgrowth.

32. REFERENCES
IMMUNOLOGY BY JANIS KUBY
ESSENTIAL IMMUNOLOGY BY IVAN ROITT
[email protected]
[email protected]
www.articles.cancer.images

33. THANK YOU!!!!!!!!!