Download 03 Anichini

09,00 – 13,40
I Sessione
Moderatori:
Giordano Beretta, Roberto Labianca
09,40 – 10,00
Il melanoma:
la biologia
Andrea Anichini
Melanomabiologyinthecontextoftumorprogression
Biologicalevents
1
2
Geneticlesionsand
Geneexpressionprofiles
Branched
evolution
Intra-tumor
heterogeneity
Phenotypicplasticity
Me
3
stroma
Interactionwith
microenvironment
Me
4
Immune
system
Mutationalload
andneoantigens
Time
Evolutionofmelanomafromprecursorlesions
Clark,1984
HumPathol1984;15:1147-65.
Miller,Mihm,2006
Shain,......Bastian
NEJM373:1926,2015
UV-induced
mutations
Authors:“AstrongsignatureoftheeffectsofUV
radiationdetectableatallevolutionarystages...
...UVradiationbothtriggersmelanomaandaccelerates
itsprogress...
...Itmeansweneedtofocusextraattentionon
protectingpre-existingmoles”
LancetOncol.17:e7,2016
Science346:945,2014.
Melanomabranchedevolution
Shain,Bastian
NEJM373:1926,2015
Genomicclassification ofcutaneousmelanoma:
fourgenomicsubtypesandthreegeneexpressionsubsets.
immune
MITF-low
keratin
Proliferation
Cellcycleprogression
Apoptosis
Geneticstability
Transcriptionalcontrol
Survival
Epigeneticregulation
Proliferation
Phenotypicplasticity:
melanomasshiftbetweenalternativetranscriptionalstates
AXLexpression
+
MITF
-
+
MITF-regulatedgenes,
pigmentationandMDAs
-
Masterregulatorsofdistincttranscriptionalstates
SOX10/MITF
Proliferativegene
network
AP-1/TEADS
Invasivegene
network
-
Shiftfromaproliferative
toinvasivegeneprograms
+
Upregulationofstemness(CD271)and
dedifferentiation(AXL)markers
-
+
Intrinsicandacquiredresistanceto
MAPKinhibition
+
-
Promotionofimmuneescapeandof
tumorinfiltrationbymyeloidcells
-
+
MelanomaplasticityaffectsresponsetoMAPKinhibitors
BRAFi
TNF-α
MITFHi
MAPKisensitive
AXLHi
MAPKiresistant
MITF/AXLalternativegeneprograms:
roleinresponsetotargettherapyandinshapingthetumormicroenvironment
AXLprogram
TiroshIetal.Science352.189,2016
MITFprogram
Targetingmelanomadedifferentiation
C-Myc
NFATc2
Brn2
MITF
TNF-α
+- GPNMB
+- RAB27a
+- PGC-1α
+- Gp100
+- Tyrosinase
+- MART-1
+- Melaninproduction
+- Pigmentation
+- Tcellrecognition
-+ CD271
TNF-RI/II
TNF-α
Perotti,Oncogene,2015
“Masterregulatorygenes”affectresponsetotargettherapy
anddevelopmentoftumorimmunity
Kaur Aetal.
APE1:endonucleaseintheDNAbase
excisionrepair(BER)pathway,
responsibleforrepairingDNAdamagedby:
oxidativestress,alkylatingagents,
andionizingradiation.
á SusceptibilitytoDNAdamage
á ResistancetoVemurafenib
á Angiogenesisandmetastasis
LossofPTENimpactsonresponsetoimmunotherapyand
contributrestoacquiredresistancetoBRAFinhibitortherapy
PengW.etal.CancerDiscovery6:202
BRFAV600E PTEN-null induciblemelanomamodel
Immunereactiontomelanocyticlesions
TheTemptationsofSaintAnthony(1512-1516)
MatthiasGrünewald Issenheimaltarpiece
ClarkWHetal.ModelpredictingsurvivalinstageImelanoma
basedontumorprogression.JNatlCancerInst.81:1893,1989.
BorroniG,VignatiG.
ShouldSuttonnevusreallybecalled
Grünewald-Suttonnevus?AmJDermatopathol.1993
ct;15(5):506-8.
DelVecchioM,MortariniR,TragniG,DiGuardoL,BersaniI,DiTollaG,
AgustoniF,ColonnaV,WeberJS,AnichiniA.T-cellactivationandmaturation
attumorsiteassociatedwithobjectiveresponsetoIpilimumabinmetastatic
melanoma. JClinOncol.29:e783-8,2011.
J.AM.ACAD.DERMATOL.
VOLUME67:583,2012
Whichantigensarerelevant?
Antigensencodedbynonmutatedgenes
(tissue-specificTAAorcancer-testisantigens)
Neoantigensresultingfromnonsynonimoussomaticmutations
Understandingmelanomabiology:thewayforwardtoimprovetreatment
Immunologyasanexample
-Neoantigenheterogeneity
-Immuneescapemechanisms.
-Masterimmunoregulatorygenes(β-catenin,COX-2..).
-Fostering“pro-immune”transcriptionalprograms..
-Preventingrecruitmentofimmunosuppressivecells.
SLAMF7
CD137
Tumor cell
NK cell
CD16
Antigen
KIR
Gene
PD-1
PD-L1
PD-L2
“mature”
CD8+ CTL
Antigen
release
Plasmacell cytokines
Dendritic cell
-PromotingDCrecruitmentattumorsite
MHC
Class I
Bcell
IL-12
PD-L1
CD80
PD-L2
CD86
MHC Class
II
CD80
CD86
PD-L1
PD-L2
TCR
CTLA-4
CD8+ “naive”
PD-1
Tcell Co-stimulatory
molecules and
inhibitory receptors
TCR
(-)
CTLA-4
PD-1
TH2(IL-4)
TH1(IFN-γ)
CD4+ Tcell (-)
Cancer–associatedfibroblasts
Immunosuppressivesubsets
CTLA-4
Treg
(CD4+ FOXP3+)
-Pro-tumoralroleofstromalcells
-Targetingimmunosuppressivesubsets
MDSCs
(HLA-DR- CD14+ CD33+)
(HLA-DR- CD15+ CD33+)