Download Basics of Cancer Immunology for StaQsQcians and ComputaQonal

10/20/16
BasicsofCancerImmunology
for
Sta:s:ciansand
Computa:onalBiologists
DonnaNeuberg,ScD
HowIt’sDone…
October19,2016
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Assump:ons
•  Wedon’thavetraininginimmunology(and
likelynotinbiologyeither)
•  Welearnaboutdisease,andabout
immunology,inresponsetothecollabora:ve
problemsconfron:ngus
•  Werarelyhavetheopportunitytodiveinto
thetopicmorebroadly
–  Ifweendupthere,weneedtomakesenseofit
Youneedascorecard
•  Whatcellsaretheplayers?
–  Myeloidcells:Dendri:ccell,macrophages,
neutrophils,mastcells,myeloid-derived
suppressorcell(MDSC)
•  Innateimmunity
–  Lymphoidcells:Tcells,Bcells,NKcells
•  Theycomeinmanyvarie:es
•  Adap)veimmunity
•  Goal:Protecttheintegrityoftheorganism
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Isapictureworth1000words?
•  Ifyouknowwhatyouarelookingat,yes!
IHCstaining
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IHCstaining
•  B-cellimmunoblas:c
lymphoma
•  T-celllymphoma
Itisnotallvisualpa[ernrecogni:on
•  Cellsurfacemarkerscandis:nguishonecellfrom
another –  CD3+CD4+isaneffector(helper)Tcell
–  CD3+CD8+isacytotoxic(killer)Tcell
–  CD19,CD20,CD22areBcellmarkers
•  CDstandsforclusterofdifferen:a:on
•  Canquan:fyabundanceofasurfacemarkerina
tumorbytallyingsinglecellswithexpression
–  Thisisflowcytometry
–  Chartslis:ngthemarkerstoexpectinagivenstate
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Cancer
•  Primarytreatmentto
•  Excisethetumor(surgery)
•  Killthetumor(radiotherapy,chemotherapy)
–  Eradicateorreducethetumorburden,sothatthe
immunesystemcantakeover
•  Cancersescapeimmunesurveillance
–  Exponen:alincreaseinunderstandofthediverse
waysinwhichcancersfoiltheimmunesystem
•  Let’sseehowtheimmunesystemworks
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Thetask
•  Immunologicalrecogni:on
–  Detectthepresenceofanenemy
•  Infec:on,cancer,etc.
•  Immuneeffectorfunc:on
–  Complementsystemofbloodproteins,an:bodies
•  Immuneregula:on
–  On/offswitch
•  Immunologicalmemory
–  Learningforthefuture
Schemaofimmunesurveillance
Ploegh,CancerImmunolRes2013
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•  Howdothecomponentsoftheimmune
systemcommunicateandac:vateone
another?
–  An:genisthemechanismofrecogni:on
–  Cuesonsurfaceofcell
•  An:gen≅pep:de≅chainofaminoacids
–  An:genispresentedandan:bodiesaremade
Lymphoidcellsneedtobeeducated
•  Naïveandmemorycells
–  Naïvecellshavenotyetseenan:gen
•  Capacitytorespondtonewchallenges
–  Memorycellshaveseentheseenemiesbefore
•  Rapidresponseteam
•  BcellsandTcellshavereceptorstograbthe
an:genandgenerateresponse
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TheBcellmechanism
•  An:genbindstotheBcellreceptor(BCR),aka
surfaceimmunoglobulin(sIg)
•  Blymphocyteproliferatesanddifferen:ates
intoplasmacells(effectorformofB
lymphocyte)
•  Plasmacellsproducean:bodies
–  SecretedformofBCR,iden:calan:genspecificity
–  An:bodiestargetthatan:gen
An:genreceptorforBcells
•  NotetheYshape.Thebaseisaconstant
region.Thereaheavyandlightchainsinthe
variableregion.
Janeway,Immunobiology
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An:genreceptorforTcells
•  Again,avariableregionandaconstantregion
Janeway,Immunobiology
Tcellsdonotbindan:gendirectly
•  Theyhavethean:genpresentedtothemby
theMHCclassIandclassIImolecules
–  CD4+cellsareeffectorTcells,MHCclassII
•  HLA-DP,DQ,DR
–  CD8+cellsarecytotoxicTcells,MHCclassI
•  HLA-A,B,C
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Wheredoesthe
an,genfit?
Spacebetweenα1
andα2isthe
bindingpocket
wherean:gensits
Β2microglobulin
meansCD8+Tcell
willformcomplex
Wikipedia
An:bodies
Ploegh,CancerImmunolRes2013
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Somanyopportuni:esforsubversion!
•  Focusonadap:veimmunity
–  Inabilitytobindan:gen
–  Inabilitytomatureandgeneratean:bodies(B)
–  InabilitytolinktoMHC(T)
•  Deficientβ2Mmeansdysfunc:onalMHCclassI,which
inturnmeansnotrainedcytotoxicTcells
•  Andwehaven’tevenlookedatwhatmakes
killingpossible
EnablingaTcelltokill
•  Complexsetofsignals—allhavetobeinplace
•  Tcellscanrespondtothes:muli,butongoing
s:mula:on:resthemout
–  Tcellexhaus:on
•  Tcelldoesnotappeartobeinherentlydeficient,but
needsrejuvena:on
•  Linkedinparttotheothersignalsthatneedtobein
place
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WherryandKurachi,NatRevImmunol2015
“Exhaustion” or “pseudoexhaustion” in CLL. Key findings of Riches et al are summarized.
Thorsten Zenz Blood 2013;121:1485-1486
©2013 by American Society of Hematology
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WherryandKurachi,NatRevImmunol2015
Howcanthingsgowrong?
Bachireddyetal.,NatRevCancer2015
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Bachireddyetal.,NatRevCancer2015
Whataboutcancerimmunotherapy?
•  Directlytargetsurfacetumoran:gens
–  Monoclonalan:bodies
•  Boostnumberandfunc:onofimmune
effectors
–  CARTcells—progenyofsuccessfulHSCT
•  Ac:vatetumoran:gen-specificimmunity
–  Vaccines
•  Overcomeinhibitoryimmunesuppression
–  Checkpointblockade
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Howdoyouseecancerimmunology?
•  Workinmelanoma?SitontheSRC/IRB?
–  Mul:plelargestudieswithcheckpointinhibitors,
ineverydiseasesiteimaginable
•  Workinmelanoma,AML,lung,renal,…?
–  Avaccinestrategyisinyourfuture
•  Workintransplant?
–  CellulartherapiessuchasCART
•  Monoclonalan:bodiesareeverywhere
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