NOTE

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

2. TOPICS INCLUDED
Thecancersoftheimmunesystem.
Howthetumorgrowthisenhancedinthebody
Tumorantigens
Inductionofimmuneresponseandparticipationofvariouscells
Eliminationoftumorandcancerouscells.
Cancerimmunotherapy

3. INTRODUCTION
Inthebodythenumberofcellsismaintainedaftermaturationbycreatingabalancebetweenthenumberofcellsproliferatedandthecellsundergoingdeath.Ifthiscontrolmechanismisdisturbedwithinthebodythenuncontrolledcellmultiplicationoccurswhichleadstothetumorousorcancerousgrowth.
Immunesystemisthedefensemechanismofthebodyagainstanyforeignparticles.

4. TUMORS OF IMMUNE SYSTEM

5. Lymphomaproliferateassolidtumorswithinalymphoidtissuesuchasbonemarrow,lymphnodesandthymus.
Leukemiacandevelopassinglecellandaredetectedbyincreaseincellnumberinbloodandlymph.
Itcanbedevelopedinmyeloidorlymphoidlineages.
Historically,itisclassifiedonthebasisofclinicalprogressionofdisease.

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

7. Chronicleukemia
Theyarelessaggressiveanddevelopslowlyandmild,barelysymptomaticdisease.
Theyariseinmaturecells.
Theseincludeschroniclymphocyticleukemia(CLL)andchronicmyelogenicleukaemia(CML).
Theyarefoundmostlyinadults.

8. ENHANCEMENT OF TUMORS
BYANTITUMORANTIBODIES
Theimmunizationofthetumoritselfsometimesdidnotprotectagainsttumorgrowth,butactuallyenhancethegrowthoftumor.
Heretheantitumorantibodiesitselfactasablockingfactor.
BYANTIGENICMODULATION
Certaintumorspecificantigensareobservedtodisappearfromthesurfaceoftumorcellsinthepresenceofserumantibodyandthentoreappear

9. aftertheantibodyisnolongerpresent.Thisphenomenoniscalledantigenicmodulation.
POOREXPRESSIONOFCLASS-IMHCMOLECULES
CD8+CTLsrecognizeantigensonlyassociatedwithclass-IMHCmolecules.
Anychangesinexpressionofclass-IMHCmoleculeswilldecreasetheCTLmediatedimmuneresponse.
Manytumorsshowsdecreaselevelofclass-IMHCmolecules.

10. ThedecreaseinitsexpressionisoftenaccompaniedbyprogressivetumorgrowthandsotheabsenceofMHCmoleculeontumorcellisgenerallyindicationofpoorprognosis.
REQUIREMENTOFSTIMULATORYANDCOSTIMULATORYSIGNALS
Activationsignal:-ItistriggeredbyrecognitionofapeptideMHCmoleculecomplexbytheT-cellreceptor.

11. Co-stimulatorysignal:-ItistriggeredbytheinteractionofB7onantigenpresentingcellswithCD28ontheT-cells.
BoththesesignalsareneededtoinduceIL-2productionandproliferationofT-cells.

12. TUMOR ANTIGENS
Twotypesofantigenshavebeenidentifiedontumorcells:
1)TumorSpecificTransplantationAntigen(TSTA)
2)TumorAssociatedTransplantationAntigen(TATA)
TSTAareuniquetotumorcellsanddonotoccuronnormalcellsinthebody.
Thesearepresentedwithclass-IMHCmolecules, includingacellmediatedresponsebytumorspecificCTLs.

13. TATAareuniquetotumorcells,theymaybeaproteinsthatareexpressedonnormalcellsduringfetaldevelopmentwhentheimmunesystemisimmatureandunabletorespond.
Reactivationoftheembryonicgenesthatencodetheseproteinsintumorcellsresultintheirexpressionofthefullydifferentiatedtumorcells.
ItisnowclearthatthetumorantigensrecognizebyhumanTcellsfallintofourmajorcategories:

14. 1)Antigensencodedbygenesexclusivelyexpressedbytumors.
2)Antigensencodedbyvariantformsofnormalgenesthathavebeenalteredbymutations.
3)Antigensnormallyexpressedatcertainstagesofdifferentiationoronlybycertaindifferentiationlineages.
4)Antigenswhichareoverexpressedinparticulartumors.

15. ManytumorantigensarecellularproteinsthatgiverisetopeptidespresentedwithMHCmolecules.
TheseantigenshavebeenidentifiedbytheirabilitytoinducetheproliferationofantigenspecificCTLsorhelperT-cells.

17. INDUCTION OF IMMUNE RESPONSE BY TUMORS
Tumorantigenscaninducebothhumoralandcell- mediatedimmuneresponsesresultinginthedestructionoftumorcells.
Amongthesethecellmediatedimmuneresponseplaysamajorrole.
ManytumorshavebeenshowntoinducetumorspecificCTLsthatrecognizetumorantigenspresentedbyclass-IMHConthetumorcells.

18. ROLE OF NK CELLS
TherecognitionoftumorcellsisnotMHCrestricted.Therefore,theactivityofthesecellsdoesnotchangebytheexpressionofMHCmolecules.
FcreceptorpresentontheNKcellsbindstoantibodycoatedtumorcellsleadingtoADCC.

19. ROLE OF MACROPHAGES
Macrophagesareobservedtoclusteraroundtumorsandtheirpresenceisoftencausetumorregression.
TheycarryoutthesamefunctionasNKcellswiththehelpofFcreceptor.
Thesecellscarryouttheirantitumoractivitybysecretinglyticenzymes,reactiveN2andO2intermediates,cytokinecalledTumorNecrosisFactor(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:-Itisaprocessbywhichapersonisprotectedfromcancergrowthandthedevelopmentoftumourimmunogenicitybytheirimmunesystem.
Ithasthreemainphases:elimination,equilibriumandescape.
Theeliminationphaseconsistsofthefollowingfourphases:
Phase1::Thefirstphaseofeliminationinvolvestheinitiationofantitumorimmuneresponse.Duringthisphase,theinfiltratinglymphocytessuchasthenaturalkillercellsandnaturalkillerTcellsarestimulatedtoproduceIFN-ϒ.

23. Phase2::NewlysynthesisedIFN-gammainducestumordeath(toalimitedamount)aswellaspromotionofchemokines.Thesechemokinesplayanimportantroleinpromotingtumordeathbyblockingtheformationofnewbloodvessels.Tumorcelldebrisproducedasaresultoftumordeathistheningestedbydendriticcells,followedbythemigrationofthesedendriticcellstothedraininglymphnodes.
Therecruitmentofmoreimmunecellsalsooccursandismediatedbythechemokinesproducedduringtheinflammatoryprocess.
Phase3::NaturalkillercellsandmacrophagestransactivateoneanotherviathereciprocalproductionofIFN-gammaandIL-12.

24. Inthedraininglymphnodes,tumor-specificdendriticcellstriggerthedifferentiationofTh1cellswhichinturnfacilitatesthedevelopmentofCD8+Tcells.
Phase4::tumor-specificCD4+andCD8+TcellshometothetumorsiteandthecytotoxicTlymphocytesthendestroytheantigen-bearingtumorcellswhichremainatthesite.
EquilibriumandEscape
Tumorcellvariantswhichhavesurvivedtheeliminationphaseentertheequilibriumphase.Inthisphase,lymphocytesandIFN-gammaexertaselectionpressureontumorcellswhicharegeneticallyunstableandrapidlymutating.

25. Tumorcellvariantswhichhaveacquiredresistancetoequilibriumthenentertheescapephase.Inthisphase,tumorcellscontinuetogrowandexpandinanuncontrolledmannerandmayeventuallyleadtomalignancies.

27. CANCER IMMUNOTHERAPY
ManipulationofCo-StimulatorySignalsCanEnhanceImmunity
Severalresearchgroupshavedemonstratedthattumorimmunitycanbeenhancedbyprovidingtheco- stimulatorysignalnecessaryforactivationofCTLprecursors(CTL-Ps).
Ashumanmelanomaantigensaresharedbyanumberofdifferenthumantumors,itmightbepossibletogenerateapanelofB7-transfectedmelanomacelllinesthataretypedfortumor-antigenexpressionandforHLAexpression.Inthisapproach,thetumorantigen(s) expressedbyapatient’stumorwouldbedetermined, andthenthepatientwouldbevaccinatedwithanirradiatedB7-transfectedcelllinethatexpressessimilartumorantigen(s).

28. EnhancementofAPCActivityCanModulateTumorImmunity
OneapproachthathasbeentriedistotransfecttumorcellswiththegeneencodingGM-CSF.Theseengineeredtumorcells,whenreinfusedintothepatient, willsecreteGMCSF,enhancingthedifferentiationandactivationofhostantigen-presentingcells,especiallydendriticcells.
Anotherwaytoexpandthedendritic-cellpopulationistoculturedendriticcellsfromperipheral-bloodprogenitorcellsinthepresenceofGM-CSF,TNF-α, andIL-4.Thesethreecytokinesinducethegenerationoflargenumbersofdendriticcells.

29. Anumberofadjuvant,includingtheattenuatedstrainsofMycobacteriumboviscalledbacillusCalmette-Guerin(BCG)andCorynebacteriumparvuum,havebeenusedtoboosttumorimmunity.
CytokineTherapyCanAugmentImmuneResponsestoTumors
cytokinesthathavebeenevaluatedincancerimmunotherapyareIFN-α,βandϒ;IL-1,IL-2,IL- 4,IL-5,andIL-12;GM-CSF;andTNF.Althoughthesetrialshaveproducedoccasionalencouragingresults,manyobstaclesremaintothesuccessfuluseofthistypeofcancerimmunotherapy.

30. INTERFERONS
Largequantitiesofpurifiedrecombinantpreparationsoftheinterferon,IFN-α,IFN-β,andIFN-ϒarenowavailable,eachofwhichhasshownsomepromiseinthetreatmentofhumancancer.
AllthreetypesofinterferonhavebeenshowntoincreaseclassIMHCexpressionontumorcells; IFN-ϒhasalsobeenshowntoincreaseclassIIMHCexpressiononmacrophages.

31. TUMORNECROSISFACTORS
Insomeinstances,thetumornecrosisfactorsTNF-αandTNF-βhavebeenshowntoexhibitdirectantitumoractivity,killingsometumorcellsandreducingtherateofproliferationofotherswhilesparingnormalcells.
InthepresenceofTNF-αorTNF-β,atumorundergoesvisiblehemorrhagicnecrosisandregression.
TNF-αhasalsobeenshowntoinhibittumor-inducedvascularisation(angiogenesis)bydamagingthevascularendothelialcellsinthevicinityofatumor, therebydecreasingtheflowofbloodandoxygenthatisnecessaryforprogressivetumorgrowth.

32. REFERENCES
IMMUNOLOGY BY JANIS KUBY
ESSENTIAL IMMUNOLOGY BY IVAN ROITT
cancerimmunology@wikepedia.com
immunology@healthcenter.uk
www.articles.cancer.images

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