Jérôme GALON

INSERM, Laboratory of Integrative Cancer ImmunologyCordeliers Research Center, Paris, France

LabEx

The immune landscape of colon cancer

ESMO Immuno-Oncology

Prague, Czech Republic,

October 2nd 2015

Disclosure

Co-founder and Chairman of the Scientific Council: HalioDx

Collaborative Research Agreement (grant) : MedImmune, Janssen, Perkin Elmer, IO biotech

Participation to Scientific Advisory Boards: ImmunID, MedImmune, Astra Zeneca, Definiens, Actelion,

HalioDx, Incyte

Consultant : BMS, Roche, GSK, MedImmune, Janssen, ImmunID,

Nanostring, Compugen

What is the relationship between tumor genotype andimmunophenotype ?

Lessons learned after 15 years of systems immunology in humantumors ? And how important is the immune system against cancer ?

How to explain “Hot” and “Cold” immune infiltrated tumors ?

Anti-PD1 treatment in CRC patients

Le et al. NEJM 2015

Cancer is one of the most complex biological system of all

“The whole is greater than the sum of its parts”, Aristotle

-> Systems biology in human cancer

Molecule X

Pathway Y

Cell Z

-> Tumor aggressiveness, progression, invasion and recurrence define early and late

stage cancers, and the severity of the disease

Definition of cancer

1) A tumor cell DNA disease – Cell-centric paradigm2) Due to the acquisition of secondary key behavioral characteristics following tumor genomic changes (Hanahan & Weinberg, Cell 2001)

TisT1 T2 T3 T4

T-Stage

N-Stage

M-Stage

Tumor invasion

Tumor progression

-> Tumor recurrence

Early-metastasis (venous emboli)

Tumor grade differentiationTumor aggressiveness(driver mutations, CIN, MSI, CIMP…)

Tumor progression, invasion and recurrence are dependent on immunity and theImmunoscore

Pre-existing immunity is determining the fate and survival of the patient, and thelikelihood of response to immunotherapy

Novel paradigm

TisT1 T2 T3 T4

T-Stage

N-Stage

M-Stage

Tumor invasion

Tumor progression

-> Tumor recurrence-> death

Early-metastasis (venous emboli)

Tumor grade differentiationTumor aggressiveness(driver mutations, CIN, MSI, CIMP…)

ImmunoscoreImmune contexture

Role of immune infiltrates in the promotion/control of early-metastatic invasion(VELIPI) in human cancers ? Impact on clinical outcome ?

Venous Emboli (VE)Lymphatic Invasion (LI) Perineural Invasion (PI)

Question

blood vessels (Endoglin)

Lymphatic vessels (PDPN)

-> Global analysis of tumor microenvironment in Human tumors

promotion control

? ?

BeneficialDetrimental No impact

?

immune

959 colorectal cancer patientsLymphatic emboli / Tumor

Memory T cells, in particular, TEM correlate with the absenceof early-metastatic invasion, and improved clinical outcomein colorectal carcinoma.

Pagès F, et al. N Engl J Med. 2005

Pagès F & Galon J. N Engl J Med. 2006

Quantification of immune cell densities (n=415 Patients, 6640 IHC) revealed themajor positive role of cytotoxic and memory T cells for patient’s survival

Galon J et al. Science 2006

ImmunoscoreImmune contexture

The foundation a new concept

Dis

ease

Fre

e S

urv

ival

0

0.2

0.4

0.6

0.8

1

0 20 40 60 80 100 120 140 160 180

Survival (months)

I

II

III

AJCC/UICC-TNMCurrent prognosis classification

Tumor Histopathologic Findings

NSIII

III

High-CD45ROCT/IM High-CD3CT/IM

Dis

ease

Fre

e S

urv

ival

0

0.2

0.4

0.6

0.8

1

0 20 40 60 80 100 120 140 160 180

Survival (months)

CD3CT/CD3IM evaluationplus

CD45ROCT/CD45ROIM evaluation

Immune cells analysis

II

III

Low-CD45ROCT/IM

Low-CD3CT/IMIV

IV

**

NS

I

Coordinated adaptive immune reaction more than tumor invasion predictsclinical outcome

->

Importance of the distribution of the adaptive immunereaction compared to tumor invasion

Galon J et al. Science 2006

Parameter

• T-stage • N-stage • Differentiation • Immune

HR

1.21.41.11.9

P value

0.250.150.840.00001

COX multivariate analysis (OS) in all stages I, II, III patients

Novel Paradigm

Galon J et al. Science 2006Galon J et al. Cancer Res. 2007

“Immune Contexture” : nature, functional orientation, density, and location within distinct tumor regions, of a natural in situ immune reaction

“Contexture: the act of assembling parts into a whole; an arrangement of interconnected parts”

Invasive margin (IM)

immune

tumor

Center of the tumor (CT)

immune

tumor

Immune ContextureParameters with major positive impact on patient’ survival

Type

Density

Functional orientation

Location • TLS (Presence and quality)

IFNGIL12TBX21IRF1STAT1

• Cytotoxic T cells (CD3, CD8)• Memory T cells (CD45RO)

TH1 cells

Associated factors

CX3CL1CXCL9CXCL10CCL5CCL2

• Center of the Tumor (CT) • Invasive Margin (IM)

CD3CT

CD3IM

CD8CT

CD8IM

CD45ROCT

CD45ROIM

1 10 100 1000 10000

Number of cells/mm2

(TH17, Treg, TH2 cells havevariable impact on survivaldepending on tumor types)

MADCAM1ICAM1VCAM1

GZMAGZMBGZMH PRFGLNY

Pages F NEJM 2005 ; Galon J. Science 2006 ; Galon J. Cancer Res. 2007 ; Camus M. Cancer Res 2009 ; Pages FJCO 2011; Mlecnik B Gastroenterology 2011; Tosolini M. Cancer Res 2011 ; Mlecnik B JCO 2011; Fridman H. Nat RevCancer 2012 ; Galon J. Immunity 2013 ; Galon J. Immunity 2013

CXCL13IL21

IL15

• Evolution of the tumor microenvironment with tumor progression?

Understanding the evolution of the immune responsewith tumor progression using systems biology

-> Spatio-temporal dynamics of the immune response with tumor progression

TisT1 T2 T3 T4∆ ∆ ∆ ∆

T-Stage

Time

• Immune escape mechanisms in human tumors?

Bindea G et al. Immunity, 2013

Neutrophils

Eosinophils

Basophils

Mast cells

Red cells

T-lymphocytes

PlasmaB cells

B-lymphocytes

NK cells

NKT cells

Macrophages

mDC

TH1

TH2

TH17

TH3

Treg

TEM

Tmemory

TEMRA

T-cytotoxic

iDC

Tumor cells

pDC

Lymph vessels

Blood vessels

Tumor microenvironment

“Immunome” of purified immune cell subpopulations

normalmucosa

Ad

ap

tive I

mm

un

ity

Inn

ate

Im

mu

nit

y

Exp

ress

ion

of

57

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es

coloncancer

aDC

Cell types (n=28)

DC

CD8 T cellsTreg

B cells

Lymph vessels

T cells

Blood vessels

SW480 cancer cells

Normal mucosa

pDCiDC

Macrophages

Neutrophils

Eosinophils

Mast cells

NK CD56bright cells

NK cells

NK CD56dim cells

TgdCytotoxic cells

TFH

T helper cells

Tcm

TemTh1 cells

Th2 cells

Th17 cells

B c

ells

#1

B c

ells

#2

Tcm

Te

mT

h1

cells

#1

Th

1 ce

lls #

2T

h2

cells

#1

Th

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lls #

2T

FH

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lls #

1T

FH

ce

lls #

2T

FH

ce

lls #

3C

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T c

ells

#1

CD

8 T

ce

lls #

2C

D8

T c

ells

#3

CD

8 T

ce

lls #

4C

D8

T c

ells

#5

Tg

d #

1T

gd

#2

NK

CD

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im c

ells

#1

NK

CD

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im c

ells

#2

NK

CD

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righ

t ce

lls #

1N

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D56

bri

ght

cells

#2

iDC

#1

iDC

#2

aDC

#1

aDC

#2

aDC

#3

aDC

#4

aDC

#5

aDC

#6

aDC

#7

aDC

#8

Eo

sino

ph

ils #

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nop

hils

#2

Ma

cro

ph

age

s #1

Ma

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#1

Ma

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#2

Ma

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#3

Ma

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#4

Neu

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#2

Neu

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ils #

3S

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#1

SW

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lls #

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#3

Nor

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#1

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#3

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11

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sa #

13

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4N

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15

Nor

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#1

6N

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sa #

17

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8N

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19

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sa #

21

Nor

ma

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#2

2Purified immune cell subpopulations : “Immunome”

Bindea G et al. Immunity 2013

Intratumor “immunome” clustering within CRC

Cluster 1 Cluster 2NC

Exp

ress

ion

of 3

72 s

igni

fican

t gen

es

with

in C

RC

tum

ors

Cluster 1 (n=60)

Cluster 2 (n=45)

Survival (Months)

Intratumor “immunome” clustering within CRC

T cellsCytotoxicityTh1

B cellsMHC Cl II

TFH cells

MHC Cl IInflammation

Group 1 Group 2P-value

CD3E <0.00001CD3G <0.0001CD4 <0.00001CD8A <0.00001GNLY <0.01GZMA <0.0001GZMB <0.01GZMH <0.0001GZMK <0.00001IFNG 0.01TBX21 <0.00001

CD19 <0.00001CD40 <0.001CD86 <0.00001HLA-DMA <0.00001HLA-DMB <0.00001HLA-DOA <0.00001HLA-DOB <0.00001HLA-DPA1 <0.00001HLA-DQA2 0.03HLA-DRA <0.00001LTA <0.00001

CXCR5 <0.0001CXCL13 <0.0001

HLA-B 0.94HLA-C 0.34IFNA1 0.23IFNA2 0.48IL1A 0.72IL1B 0.81IL8 0.84IL8RA 0.50

-> “Immunome” analysis from CRC tumors reveals functional association of Tcells, cytotoxicity, B cells, MHC Cl II molecules, and TFH cells

Bindea G et al. Immunity 2013

CD1A ENGGranulocyteIL3RA PDPN /csCD20 /cs CD68 /Tum

CD45RO FoxP3 TryptaseCD3 / Tum CD57 /cs CXCR5CD8 /Tum

Intratumor innate cells, adaptive cells, and vessels

IHC enzymatic stainings: -> Quantification (cells/mm2)Cohort 1 (n=120 patients), cohort 2 (n=415 patients)

Bindea G et al. Immunity 2013

Intratumor B cells, T cells and TFH cells

CD20

CD3 CXCR5

Bindea G et al. Immunity 2013

CD3

FoxP3

CD20

CD8extra

CD8intra

CD68intra

CD68

CD45RO

PDPN

CD57

CXCR5

Granulocyte

IL17

ENG

Tryptase

IL3RA

CD1A

CD3

FoxP3

CD20

CD8extra

CD8intra

CD68intra

CD68

CD45RO

PDPN

CD57

CXCR5

Granulocyte

IL17

ENG

Tryptase

IL3RA

CD1A

CD8

CD8

Invasive margin (IM)Center of the tumor (CT)

Cell density

x-y-Force Directed Topology

Cell density(cells/mm2)

tumor progression

Understanding the evolution of the immune responsewith tumor progression : The immune landscape

Bindea G et al. Immunity 2013

TFH

B-cells

CD3

FoxP3

CD20

CD8extra

CD8intra

CD68intra

CD68

CD45RO

PDPN

CD57

CXCR5

Granulocyte

IL17

ENG

Tryptase

IL3RA

CD1A

CD3

FoxP3

CD20

CD8extra

CD8intra

CD68intra

CD68

CD45RO

PDPN

CD57

CXCR5

Granulocyte

IL17

ENG

Tryptase

IL3RA

CD1A

CD8

CD8

Invasive margin (IM)

Center of the tumour (CT)

Cell density

x-y-Force Directed Topology

CD3

FoxP3

CD20CD8extra

CD8intra

CD68intra

CD68

CD45RO

PDPN

CD57

CXCR5

Granulocyte

IL17

ENG

Tryptase

IL3RA

CD1A

CD3

FoxP3

CD20

CD8extra

CD8intra

CD68intra

CD68

CD45RO

PDPN

CD57

CXCR5

Granulocyte

IL17

ENG

Tryptase

IL3RA

CD1A

CD8

CD8

Invasive margin (IM)Center of the tumor (CT)

Impact on DFS

x-y-Force Directed Topology

Hazard ratiotumor recurrence

Understanding the evolution of the immune responsewith tumor progression : The immune landscape

GoodBad

Bindea G et al. Immunity 2013

TFH

B-cells

TH17

TH1

Tumor

TFH

CXCL13

Tmemory

T-cytotoxic

B cells

IL21

TLS

Immune contexture associated with prolonged survival

TLSInvasivemargin

Tumor

Tumor

Tumorstroma

Bindea G et al. Immunity 2013

• Mutation, immunogenicity and immune microenvironment?

Relationship between molecular phenotypes andimmunophenotypes of CRC tumors using systems biology

-> Rationale for an immune classification of tumors

• Immune escape mechanisms in human tumors?

Angelova M et al. Genome Biol, 2015

Mutations Immune

Spin chart from (n=460 patients)

Molecular phenotypes and immunophenotypes of CRC tumors

Molecular phenotype

Angelova M et al. Genome Biol. 2015

Immunome of CRC tumors

Molecular phenotype

Spin chart from (n=460 patients)

Molecular phenotypes and immunophenotypes of CRC tumors

Angelova M et al. Genome Biol. 2015

Spin chart from (n=460 patients)

Molecular phenotypes and immunophenotypes of CRC tumors

Innate immunity

Adaptive immunity

Enrichment of immune subpopulations : TILs in 97% of tumors, and T-cells in 69% of tumors

metagenes expression profiles

Enriched and depleted immune subpopulations in hypermutated(MSI-H and MSS^)

Volcano plots for enriched (blue) and depleted (yellow) TIL subpopulations in the distinctpatient groups compared to normal samples (n=50).

MSI-H MSS^

Tregs and MDSCs are depleted

EnrichedDepleted

Act CD4Act CD8Tem CD4Tem CD8Tregs MDSCs

MSI-HMSS^

Angelova M et al. Genome Biol. 2015

Patient 1 (weak) Patient 2 (moderate) Patient 3 (strong)

How to explain “Hot” and “Cold” immune infiltrated tumors ?

CD3Tumor

Median OS (death)

< 2 years 4.9 years > 15 years

Im0 Im2 Im4ImmunoscoreCD3/CD8Center/Margin

Mechanisms associated with T cells infiltration

Attraction Adhesion

MADCAM1VCAM1ICAM1

T cells

TH1Cytotoxic

MemoryT cells

CXCL9CXCL10

CCL2CCL5

CX3CL1 CXCL13

TFHB cells

Mlecnik et al. Gastroenterology 2010

Bindea et al. Immunity 2013

IL15 and intratumoral immune reaction

In situ densities of proliferating B and T cells

CD20+ CD3+ Ki67+

-> Quantification in tumor core (CT), invasive margin (IM), and lymphoid ilets (LI)

Mechanisms associated with T cells infiltration

Attraction Adhesion

MADCAM1VCAM1ICAM1

T cells

TH1Cytotoxic

MemoryT cells

CXCL9CXCL10

CCL2CCL5

CX3CL1 CXCL13

TFHB cells

Mlecnik et al. Gastroenterology 2010

Local lymphocyteproliferation

IL15

Mlecnik et al. Science Transl Med 2014

Bindea et al. Immunity 2013

Implications for cancer classification and therapies

To the Immunoscore

From the Immune contexture

(A simple and powerfull Immune Test)

(Complexity of intratumor immune reaction)

T-STAGE N-STAGE M-STAGETumor cell extension and invasion

CD3+ T cells CD8+ T cells Density Locaton (CT, IM)ImmunoscoreHost immune response

Mucinous CCS1

CCS2Medullary

Adeno. NOS

Serrated

Signet ring cell

Enterocyte

Goblet-like

Transit-amplifying-S

Infammatory

Stem-like

CIN

MSI

CIMP CCS3Transit-amplifying-R

BRAF

APC

KRAS

TP53

Morphology Cell of origin Molecular pathway Mutaton status Gene expression

Tumor cell characteristcs

Ways to classify

CTNNB1

Micropapillary

Cribriform comedo-type

Galon et al. J Pathol. 2014

Colorectal cancer classifications

Prolonged survival in patients with high Immunoscore (Im) based on the evaluation of CD45RO-CT/IM and CD8-CT/IM

Mlecnik et al. J Clin Oncol 2011

Survival (months)

P<0.0001

Dis

ease

-Fre

e Sur

viva

l (%

)

0

20

40

60

80

100

0 20 40 60 80 100 120 140 160 180

Im4

Im2

Im1Im0

Im3

AJCC/UICC-Stage I-III

Dis

ease

-Fre

e Sur

viva

l (%

)

Im4

Im2

Im1Im0

Im3

0

20

40

60

80

100

0 20 40 60 80 100 120 140 160 180

Survival (months)

P<0.0001

AJCC/ UICC-Stage I-IV

Multivariate proportional hazard COX analysis among all patients with AJCC/UICC-TNM Stage I/II/III colorectal cancer

Tumor (T) stageN StageGenderNumber of total lymph nodesHistological gradeMucinous ColloideOcclusionPerforationImmunoscore

Log Rank P-values

1.241.311.471.130.691.291.034.030.65

0.290.170.180.680.290.470.940.00840.0003

HRCOX analysis for DFS

According to clinical parameters and immune parameters

DFS OS DSS

1.38

0.64

0.09 ns

<0.0001

1.18

0.71

0.29 ns

<0.0001

1.43

0.63

0.10 ns

<0.0001

HR P-value HR P-value HR P-value

AJCC/UICC-TNM

Immunoscore

COX analysis

According to AJCC/UICC-TNM classification and immune score

-> Validation in 2 independent cohorts of colorectal cancer patientsMlecnik et al. J Clin Oncol 2011

Metastasis analysis

Colorectal cancer

Liver Metastasis Lung Metastasis

One primary tumor

Multiple metastatic sites

Immunoscore within multple metastases at diferent sites Death at years: Low Immunoscore: 76% vs High Immunoscore: 15%

THE IMMUNOSCOREAS A NEW POSSIBLE APPROACH IN THECLASSIFICATION OFCANCER

Naples, Italy, Feb 2012Principal investigator: J. Galon

Galon J et al. J. Transl. Med. 2012Galon J et al. J. Pathol. 2014

The IMMUNOSCORE

FaisabilityIHC automate High-resolution scanner

whole slide quantification

Digital pathology

Immunoscore

-> Standardized Operating Procedure-> Today’s tools for modern pathologists

Galon J et al. J. Transl. Med. 2012Galon J et al. J. Pathol. 2014

Immunoscore (I) using whole slide FFPE

Routine whole slide stainings & precise image quantification

CT

IM

Tissue

Immunostaining Definition of Tumor Regions

Density plots

I

CD3

World Immunotherapy Council inaugural meeting (Feb 2012)

Support (moral) from the World Immunotherapy Council (WIC), and supportfrom societies including, EATI, BDA, CCIC, CIC, CRI, CIMT, CSCO, TIBT,DTIWP, ESCII, NIBIT, JACI, NCV-network, PIVAC, ATTACK, TVACT…

Worldwide Immunoscore consortium (PI: J Galon)

The Immunoscore as a New Possible Approach for theClassification of Cancer

Assay harmonization

Immunoscore meetings :-Feb 2012, Italy-Dec 2012, Italy-Nov 2013, SITC, USA-Dec 2013, Italy-Jan 2014, Qatar-Jul 2014, Paris, France-Nov 2014, SITC, USA-Nov 2015, SITC, USA-Dec 2015, Italy

Switzerland

Australia

Netherland

Spain

Qatar

Canada

Japan

China

Immunoscore

Italy

Austria

Germany

Sweden

FranceUSA

UKCzech R

India

Switzerland

(23 Centers, 17 countries: >3000 patients)

PI: J Galon SITC, EATI23 Centers, 17 countries

National Prospective Immunoscore Consortium

Worldwide Immunoscore Consortium

European Immunoscore Consortium

PI: J Galon ERAnet H20205 European countries

PI: F PagèsPHRC, INCa6 hospitals

Switzerland

Australia

Netherland

Spain

Qatar

Canada

Japan China

Immunoscore

Italy

Austria

Germany

Sweden

France

USA

UKCzech

India

Ongoing international consortia on Immunoscore

Functional orientation

IFNGIL12TBX21IRF1STAT1

MADCAM1ICAM1VCAM1ITGAE

Quantification (cells/mm2)

Adaptive immunity, cytotoxic, memory T cells

Tumor center, Margin, Tertiary lymphoid ilets

Immune contexture

CX3CL1CXCL9CXCL10CCL5CCL2

GZMAGZMBGZMH PRFGLNY

Type

Density

Location

The immune landscape in human tumors, and definition of the immune contexture

CXCL13

Galon J et al. Immunity 2013

TFH cells, B cells

IL21, IL15

Functional orientation

IFNGIL12TBX21IRF1STAT1

MADCAM1ICAM1VCAM1ITGAE

Quantification (cells/mm2)

Adaptive immunity, cytotoxic, memory T cells

Tumor center, Margin, Tertiary lymphoid ilets

Immune contexture

Immunologic Constant

of Rejection (other diseases)

CX3CL1CXCL9CXCL10CCL5CCL2

GZMAGZMBGZMH PRFGLNY

Cancer

Type

Density

Location

Immunoscore

The overlap between the immune contexture, theimmunologic constant of rejection and the Immunoscore

CXCL13

Galon J et al. Immunity 2013

IL21, IL15

Stratification of cancer based on the immune status

MSI-H MSS^ MSS/CIMP.hi MSS MSS-CIMP.lo

Tumor classification

Immune classification

IMMUNE

-> Importance of having standardized immune Assays

Towards the future

1) Prognostic: ImmunoscoreTM - “I”

Immune Contexture • Nature • Functional orientation • Density• Location

• Cytotoxic & Memory T cells• Prognostic value: “I” > TNM • Tumor invasion parameters (T, N, …) are statistically dependent on “I”

-> Novel cancer classification

2) Predictive markers• Current clinical trials

3) Patient stratification Based on immune contexture defect

4) Novel immunotherapies Adapted to patient’s immune defect

Galon J et al. Immunity 2013

Franck Pagès Angela VasaturoTessa Fredriksen Helen AngellStéphanie Mauger Mihaela Angelova Florence Marliot Sarah ChurchLucie Lafontaine Pauline MabyAmélie Bilocq Marc Van den EyndeAmos Kirilovsky Bernhard MlecnikMarie Tosolini Gabriela Bindea

Anne Berger

Anna ObenaufMichael Speicher

Tchao MeatchiChristine LagorcePatrick Bruneval

Galon lab. INSERM, CRC, Paris, France

Dpt. of General and Digestive Surgery,HEGP, Paris, France

Institute for Genetics, Graz, Austria

Dpt. of Pathology, HEGP, Paris, France

Philippe Wind

Dpt. Digestive Surgery and Pathology, Avicenne, Bobigny, France

Team 13, Cordeliers Research Center, France

Hervé Fridman

Martin Asslaber

Dpt. Pathology, Graz hospital, Graz, Austria

Dpts. of Pathology from the 23 CentersWorldwide

SITC, EATI and all supportive societiesDefiniens, PathForce, MedImmune

Pornpimol CharaoetongZlatko Trajanoski

Institute for Bioinformatics, Innsbruck, Austria

University Clinic, Erlangen, Germany

Christopher BeckerMaximilian Waldner

Jean Baptiste Latouche

Rouen University, France

Anna BerghoffMatthias Preusser

Clinical Division of Oncology, Medical Universityof Vienna, Austria

Team 10, Cordeliers Research Center, France

Gauthier StollGuido Kroemer

Jérôme GALON

INSERM, Laboratory of Integrative Cancer ImmunologyCordeliers Research Center, Paris, France

LabEx

The immune landscape of colon cancer

ESMO Immuno-Oncology

Prague, Czech Republic,

October 2nd 2015