Escape immune surveillance. Tumor-immune system crosstalk. The hallmarks of cancer. Escape immune surveillance

Tumor-immune system crosstalk Christos Tsatsanis The hallmarks of cancer • • • • • • Growth self-sufficiency Evade apoptosis Ignore anti-proliferati...
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Tumor-immune system crosstalk Christos Tsatsanis

The hallmarks of cancer • • • • • •

Growth self-sufficiency Evade apoptosis Ignore anti-proliferative signals Limitless replication potential Sustained angiogenesis Invade tissues

• Escape immune surveillance

Escape immune surveillance • Immunoselection/immunoediting • Immunosubversion

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Tumor-immune system crosstalk

A. Immune cell actions against tumor cells

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How important is the immune system in cancer development and progression?

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Mechanisms of cancer immunosurveillance: CD8+ CTLs

Mechanisms of cancer immunosurveillance: antigen recognition; Th1/Th2

Mechanisms of cancer immunosurveillance: dendritic cells

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Mechanisms of cancer immunosurveillance: NK cells

Mechanisms of cancer immunosurveillance: NKT cells

Mechanisms of cancer immunosurveillance: indirect destruction via antigen presentation

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Mechanisms of cancer immunosurveillance: tumor-specific antibodies

B. Tumor cells talk to immune cells

• Tumor cells express molecules on their cell surface that affect the immune response (i.e antigens, death receptors etc.) • Tumor cells secrete factors that affect the immune response (cytokines, growth factors, hormones, neuropeptides)

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Links between endogenous tumor suppression and immunosurveillance

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Mechanisms of tumor escape from the immune system: IFN-insensitivity, antigen presentation

Mechanisms of tumor escape from the immune system: recruitment of myeloid suppressor cells

Mechanisms of tumor escape from the immune system: regulatory T-cells and production of IDO from DCs

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Mechanisms of tumor escape from the immune system: the role of pDCs

Mechanisms of tumor escape from the immune system: induction of T-cell anergy by immature DCs

Mechanisms of tumor escape from the immune system: induction of T-cell apoptosis via PD1 and Fas

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Mechanisms of tumor escape from the immune system: suppression of CTLs by IL-13 and TGFb

Mechanisms of tumor escape from the immune system: recruitment of VLCs and pDCs, induction of angiogenesis and inflammation

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Impact of inflammation in cancer progression

TLR signals reverse Treg-mediated suppression

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Lymphagiogenesis in cancer- the road to metastasis

VEGF-C/D: mediators of lymphagiogenesis

Tumor cells metastasize via sentinel lymph nodes

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Proximal lymph nodes are immunosuppressed

Variation in cell number and composition in proximal lymph nodes

Dendritic cells in sentinel lymph nodes

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Immunotherapy in cancer

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Impact of stress in tumor growth and the anti-tumor immune response

Stress alters T-cell profile in tumor bearing animals

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Stress results in increased tumor size

Stress induces mdr1 expression and drug resistance

Stress neuropeptides in cancer

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Response to stress: Stress

CRF

HPA axis

The nervous, endocrine and immune systems form the core of an adaptation mechanism to exogenous or endogenous stresses

Sources of CRF peptides in the periphery include:

Neurons: peripheral innervation (including autonomic) Epithelial cells in:

Immune cells:

™adrenals ™skin ™gastrointestinal tract ™gonads ™endometrium ™placenta

™Mast cells ™Macrophages ™T-cell ™Spleen ™Thymus

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CRF Receptors

Έκφραση του CRF σε καρκινικά κύτταρα • CRF εκφράζεται στο 30% καρκίνων του µαστού. • Έχει βρεθεί να εκφράζεται σε µελανώµατα • Καρκίνοι του προστάτη υπερεκφράζουν CRF (συχνά συνδέονται µε εµφάνιση συνδρόµου Cushing) • CRF υπερεκφράζεται σε µικροκυτταρικούς καρκίνους του πνεύµονα • Εκφράζεται σε ενδοκρινείς καρκίνους του παγκρέατος, του εντέρου, φαιοχρωµοκυτώµατα. • H κυτταρική σειρά καρκίνου ενδοµητρίου Ishikawa εκφράζει CRF

Επαγωγή της κινητικότητας των MCF7 κυττάρων από τον CRF (συνθήκες χωρίς ορό)

distance % of average

CRH 120 100 80

control

60

CRH

40 20 0 0hrs

3hrs

6hrs

12hrs

24hrs

Hours

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control

CRF peptides induce TLR4 expression and augment LPS-induced cytokine production CRF peptides

CRF 32.4%

18.7%

Labelled oligo CRF UCN1 UCN2

CRF2

Cold wt competitor wt wt wt wt mt wt wt wt wt wt - + - - + + + + + + - + - - - - - - - - + - -

LPS

UCN1

UCN2

40.5%

39.8%

PU.1

cells

TLR4

Labelled oligo CRF UCN1 UCN2

PU.1

1.8%

Cold wt competitor wt wt wt wt mt wt wt wt wt - + - - + + + + + - + - - - - - - + - - - -

Macrophage activation

AP-1

pro-inflammatory pro(IL-6, - TNF-α, IL-1β) cytokine production

AP-1 Tlr4 promoter-luc (fold difference)

7 6 5 4 3 2 1 0 NP

control

UC N1

UCN2

C RF

AP-1 PU.1

Delta Rn

10

TLR4 mRNA

CRF

1

UCN1 UCN2 Control

10-1

LPS

10-2

TLR4 promoter

10-3

J. Immunol. 2006

Cycle number

LPS UCN CRF

CRF1

LPS UCN1

2000

UCN2

TLR4

1500

1000

CRF

+

+

+

+

-

-

+

-

-

+

-

-

+

-

-

-

500

pCREB

0

TNFα TNFα inhibition

t-CREB

cytoplasm I L - 6 ( p g p e r m g o f p r o te in )

800 700 600 500 400 300 200 100 0

LPS UCN1

lps

u+l

uII+l

ILIL-6 induction

UCN2 CRH

+

+

+

+

-

+

-

-

-

-

+

-

-

-

-

+

c+l

pPI3k

CREB

PI3K/Akt

Actin

LPS UCN1

-

PGE2

+ +

+ -

CoxCox-2 PGE2 (pg/mg of protein)

TNF--α (pg/ml) TNF

2500

CRF2

3h

-

+ -

+ +

6h

120

**

100 80

*

*

60 40 20 0 LPS

UCN1+LPS

UCN2+LPS

CRF+LPS

J. Cell. Physiol. 2007

Effects of CRF receptor signals on activated macrophages: CRF

UCN1

CRF1

Stimulation of proinflammatory cytokine production via upregulation of TLR4

UCN2

CRF2

Enhancement of PGE2 formation via Induction of Cox-2

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