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10/20/16 BasicsofCancerImmunology for Sta:s:ciansand Computa:onalBiologists DonnaNeuberg,ScD HowIt’sDone… October19,2016 1 10/20/16 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 2 10/20/16 Isapictureworth1000words? • Ifyouknowwhatyouarelookingat,yes! IHCstaining 3 10/20/16 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 4 10/20/16 Cancer • Primarytreatmentto • Excisethetumor(surgery) • Killthetumor(radiotherapy,chemotherapy) – Eradicateorreducethetumorburden,sothatthe immunesystemcantakeover • Cancersescapeimmunesurveillance – Exponen:alincreaseinunderstandofthediverse waysinwhichcancersfoiltheimmunesystem • Let’sseehowtheimmunesystemworks 5 10/20/16 Thetask • Immunologicalrecogni:on – Detectthepresenceofanenemy • Infec:on,cancer,etc. • Immuneeffectorfunc:on – Complementsystemofbloodproteins,an:bodies • Immuneregula:on – On/offswitch • Immunologicalmemory – Learningforthefuture Schemaofimmunesurveillance Ploegh,CancerImmunolRes2013 6 10/20/16 • 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 7 10/20/16 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 8 10/20/16 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 9 10/20/16 Wheredoesthe an,genfit? Spacebetweenα1 andα2isthe bindingpocket wherean:gensits Β2microglobulin meansCD8+Tcell willformcomplex Wikipedia An:bodies Ploegh,CancerImmunolRes2013 10 10/20/16 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 11 10/20/16 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 12 10/20/16 WherryandKurachi,NatRevImmunol2015 Howcanthingsgowrong? Bachireddyetal.,NatRevCancer2015 13 10/20/16 Bachireddyetal.,NatRevCancer2015 Whataboutcancerimmunotherapy? • Directlytargetsurfacetumoran:gens – Monoclonalan:bodies • Boostnumberandfunc:onofimmune effectors – CARTcells—progenyofsuccessfulHSCT • Ac:vatetumoran:gen-specificimmunity – Vaccines • Overcomeinhibitoryimmunesuppression – Checkpointblockade 14 10/20/16 Howdoyouseecancerimmunology? • Workinmelanoma?SitontheSRC/IRB? – Mul:plelargestudieswithcheckpointinhibitors, ineverydiseasesiteimaginable • Workinmelanoma,AML,lung,renal,…? – Avaccinestrategyisinyourfuture • Workintransplant? – CellulartherapiessuchasCART • Monoclonalan:bodiesareeverywhere 15