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Kidney cancer and melanoma: progresses in clinical and translational research. ROME, November 23-24, 2007. EPIGENETIC IMMUNOTHERAPY OF HUMAN MELANOMA: MOLECULAR BASES AND PERSPECTIVE CLINICAL APPLICATIONS. Luca Sigalotti Cancer Bioimmunotherapy Unit,

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slide1

Kidney cancer and melanoma:

progresses in clinical and translational research

ROME, November 23-24, 2007

EPIGENETIC IMMUNOTHERAPY OF HUMAN MELANOMA: MOLECULAR BASES

AND PERSPECTIVE CLINICAL APPLICATIONS

Luca Sigalotti

Cancer Bioimmunotherapy Unit,

Centro di Riferimento Oncologico, I.R.C.C.S,

Aviano

slide3

EPIGENETICS

Heritable changes in the expression

of single genes or patterns of genes

not based on modifications of the DNA sequence

Methylation in C5 of cytosine within CpG dinucleotides

Histone modifications

Changes in chromatin structure

TO TRANSCRIBE OR NOT TO TRANSCRIBE ?

slide4

Morgan et al., Hum Mol Genet (2005)

Hypomethylation

(gene expression)

Hypermethylation

(gene silencing)

slide5

GENETIC ALTERATIONS

EPIGENETIC ALTERATIONS

DYNAMIC

IRREVERSIBLE

slide6

EPIGENETIC MODIFICATIONS

ARE REVERSIBLE PHARMACOLOGICALLY

Inhibitors of DNMT (e.g., 5-AZA-cytidine, 5-AZA-2’- deoxycytidine, Zebularine)

Inhibitors of HDAC (e.g., TSA, depsipeptide, SAHA,….)

slide8

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DNMT

DNMT

DNMT

DNA

replication

5-AZA-CdR

DNA

methylation

X

X

Hypomethylated DNA

slide9

Epigenetically-regulated

immune molecules

in cutaneous melanoma

slide10

CYTOTOXIC T CELLS AND/OR

ANTIBODY-DEFINED TUMOR-ASSOCIATED ANTIGENS

slide11

CANCER TESTIS ANTIGENS (CTA)

Different families of related antigens: MAGE, NY-ESO and SSX gene families and GAGE/PAGE/XAGE super-families ………..

slide13

EXPRESSION OF MAA IN SEQUENTIAL

AND CONCOMITANT MELANOMA METASTASES

slide16

CO-EXPRESSION OF 7 CTA

IN 53 METASTATIC MELANOMAS

7CTA

(0 %)

6CTA

(9 %)

0 CTA

(11 %)

5 CTA

(9 %)

1 CTA

(24 %)

4 CTA

(13 %)

3 CTA

(13 %)

2 CTA

(21 %)

slide20

REGULATION OF CTA EXPRESSION

IN HUMAN MELANOMA XENOGRAFTS BY 5-AZA-CdR

slide21

NY-ESO-1 mol/b-actin mol

PERSISTENCY OF 5-AZA-CdR-INDUCED CTA EXPRESSION IN HUMAN MELANOMA XENOGRAFTS

slide22

IN VIVO GENERATION OF ANTI-NY-ESO-1 ANTIBODIES BY 5-AZA-CdR-TREATED MELANOMA CELLS

OD405

slide23

INTRATUMOR

HETEROGENEITY

slide24

LEVELS OF MAGE-A3 mRNA EXPRESSED BY DIFFERENT SINGLE CELL CLONES

FROM MEL 313 MELANOMA CELL LINE

7

5

MAGE-3 mol/b-actin mol (x10-3)

3

1

Mel 313

cell line

1

2

3

4

5

6

7

8

9

10

11

12

13

14

Clone

slide25

CLONE 5

CLONE 14

ANALYSIS OF MAGE-A3 PROMOTER METHYLATION

IN MEL 313 MELANOMA CLONES

slide26

1,6x10-2

1,2x10-2

8x10-3

4x10-3

0

UP-REGULATION OF MAGE-3 EXPRESSION

IN SINGLE CELL CLONES

FROM MEL 313 MELANOMA CELL LINE BY 5-AZA-CdR

3x10-3

MAGE-3 mol/b-actin mol

2x10-3

1x10-3

0

Clone 5

Clone 14

slide27

RECOGNITION OF MEL313 MELANOMA CLONES BY

A MAGE-3-SPECIFIC HLA-B37-RESTRICTED CTL CLONE

slide29

EFFECT OF 5-AZA-CdR ON LEVELS OF HLA CLASS I AND

CO-STIMULATORY MOLECULES IN MEL 275 MELANOMA CELLS

slide30

30

Ctrl

5-AZA-CdR

20

% Lysis

10

0

25:1

12:1

6:1

3:1

1.5:1

E:T ratio

RECOGNITION OF HLA-A2-POSITIVE MEL 275 MELANOMA CELLS BY AN ANTI-GP100 CTL CLONE

slide31

ENHANCED AMOUNT OF IFN-g RELEASING GP100-SPECIFIC HLA-A2- RESTRICTED CTL IN RESPONSE TO 5-AZA-CDR-TREATED

MEL 275 MELANOMA CELLS

5-AZA-CdR

a-HLA

Class I

a-ICAM-1

slide32

DE NOVO EXPRESSION OF CTA IN AML AND MDS PATIENTS TREATED WITH A SINGLE COURSE OF 5-AZA-CdR

T: indicates time (days) from the beginning of Decitabine treatment

slide34

apoptosis

cell cycle

angiogenesis

invasion &

metastasis

immune

recognition

PHARMACOLOGIC DNA HYPOMETHYLATION

AS A “POSITIVE” REGULATOR

OF THE BIOLOGY OF CANCER CELLS

Epigenetic drugs

slide35

Systemic

Administration

of 5-AZA-CdR

Methylation

“Epigenetic”

chemoimmunotherapy

CTA-based

Vaccine(s)

slide36
Maresa Altomonte

Lucia Anzalone

Edi Bolzanaro

Lorelai Brasoveanu

Luana Calabrò

Ilaria Cattarossi

Francesca Colizzi

Enzo Cortini

Sandra Coral

Alessia Covre

Riccardo Danielli

Chiara De Nardo

Anna Maria Di Giacomo

Elisabetta Fratta

Ester Fonsatti

Massimo Guidoboni

Annunziata Gloghini

Elda Lamaj

Antonia Anna Lettini

Samuele Massarut

Giampaolo Nardi

Hugues Nicolay

Laura Pezzani

Cristina Santantonio

Luca Sigalotti

Daniela Marconi

MEDICAL ONCOLOGY AND IMMUNOTHERAPY DEPT. OF MEDICAL ONCOLOGYUNIVERSITY HOSPITAL OF SIENA CANCER BIOIMMUNOTHERAPY UNITDEPT. OF MEDICAL ONCOLOGY, CRO AVIANO