Présentation 2

STAT3 as a target in
Immunotherapy
Oncology & Immunology
SBIM M2
0
Arpigny Esther
Transcription Factor STAT3
Differentiation
Cell proliferation Apoptosis
STAT3
Angiogenesis Survival
Immunosuppression
1
Revisiting signal transducer and activator of transcription 3 (STAT3) asan anticancer target and its inhibitor discovery: Where are we andwhere should we go?, 2019, https://doi.org/10.1016/j.ejmech.2019.111922
STAT3 Pathway
2
Zouet al. Molecular Cancer, Targeting STAT3 in Cancer Immunotherapy, 2020, https://doi.org/10.1186/s12943-020-01258-7
STAT3 Pathway
Under physiological
conditions,
Very controlled pathway
3
STAT3 Pathway
PIAS
PTPases
SOCS
4
Dysregulated
STAT3
STAT3 is deregulated in many cancers
Zouet al. Molecular Cancer, Targeting STAT3 in Cancer Immunotherapy, 2020, https://doi.org/10.1186/s12943-020-01258-7 5
Why target
STAT3 ?
• Play a role in tumor formation
• Metastases
• Resistance to treatment
• Poor clinical prognosis
• Large role in immunosuppression
STAT3 is a very interesting target for immunotherapy
STAT3 on the TME
What are the constituents of the Tumor Microenvironment ?
7
Immunomodulatory Function of the Tumor Suppressor p53 in Host Immune Response and the Tumor Microenvironment, 2016, https://doi.org/10.3390/ijms17111942
STAT3 on the TME
Tumor-infiltrating
immune cells Smooth muscle
cells
Cancer-
associated
fibroblasts CAFs
Tumor cells
Endothelial cells
8
STAT3 on the TME
STAT3 overexpressed in tumor cells, tumor-infiltrating

immune cells and in CAFs
STAT3 modulates the microenvironment
STAT3 on the immune system
STAT3 induces immunosuppression – HOW ?
o Promote expression of immunosuppressive factors (Il6, Il10)

o Impairs the production of proinflammatory mediators (IFNg)
o Reduces mechanism of antigen presentation,

o Inhibits tumor killing activities by cytotoxic cells and slow down dendritic cells
maturation
o Inhibit innate and adaptative immune responses in tumor-infiltrating immune

cells
10
STAT3 Inhibition
How could we inhibit STAT3 ?
11
STAT3 Inhibition
1) Target molecules upstream

à Not specific enough
12
STAT3 Inhibition
2) Target STAT3 itself
13
How to inhibit STAT3 ?
14
Qinet al., STAT3 as a potential therapeutic target intriple negative breast cancer: a systematic review, 2019, https://doi.org/10.1186/s13046-019-1206-z
Direct
STAT3
inhibitors
FDA • Celexocib (Colorectal cancer)
approved
• BBI608 (Colorectal cancer)
• Pyriméthamine (CLL chronic lymphoid

leukemia, Small lymphocytic lymphoma)
15
Stat 3
inhibitors
in clinical
trials
16
TNBC Triple-Negative Breast Cancer
o Most aggressive and mortal subtype of breast cancer
o 15% of breast cancers

o High incidence-to-mortality ratio (approximately 50%)
Commonly diagnosed
in young women
< 40 years
Qinet al., STAT3 as a potential therapeutic target intriple negative breast cancer: a systematic review, 2019 , https://doi.org/10.1186/s13046-019-1206-z 17
Meta-Analysis of Prevalence of Triple-NegativeBreast Cancer and Its Clinical Features at Incidence in Indian PatientsWith Breast Cancer, 2020 Jul 8.doi: 10.1200/GO.20.00054
TNBC Triple-Negative Breast Cancer
o Lack of expression of estrogen receptor (ER), progesterone receptor (PR),
and human epidermal growth factor receptor 2 (HER2)
o Complex heterogeneity
o Absence of molecular targets
o No effective targeted therapy valited
o Current treatment = chemotherapy
Urgent need for biomarkers and novel targets

Qinet al., STAT3 as a potential therapeutic target intriple negative breast cancer: a systematic review, 2019 , https://doi.org/10.1186/s13046-019-1206-z 18
Meta-Analysis of Prevalence of Triple-NegativeBreast Cancer and Its Clinical Features at Incidence in Indian PatientsWith Breast Cancer, 2020 Jul 8.doi: 10.1200/GO.20.00054
Why STAT3 inhibitors are still in clinical trials for TNBC ?
o Lack of molecular targets in TNBC
o Toxicity of indirect STAT3 inhibitors
o Generate a direct STAT3 inhibitor is a big challenge
19
STAT3 in TNBC
STAT3 oncogene is overexpressed and constitutively activated in
TNBC and is associated with the high metastatic risk and poor survival
outcomes
Pivotal role of STAT3 in the initiation,

progression, metastasis, and immune evasion
20
STAT3 pathway in TNBC
21
STAT3 as a potential therapeutic target intriple negative breast cancer: a systematic review, 2019; https://doi.org/10.1186/s13046-019-1206-z
Article analysis : Blockade of STAT3 induces cellular senescence
22
Blockade of Stat3 oncogene addiction induces cellular senescence and reveals acell-nonautonomous activity suitable for cancer immunotherapy, 2020, https://doi.org/10.1080/2162402X.2020.1715767
1. Inhibition of STAT3 in cancer cells where STAT3 is

constitutively activated
Induces senescence
SASP
STAT3 Generate an
secretory
inhibition immunotherapy
phenotype
“SASP-siSTAT3”
Cancer cells
23
STAT3 dependent
Article
Blockadeanalysis
of STAT3 inducesofcellular
: Blockade senescence
STAT3 induces cellular senescence
In vitro
2. In vitro
TNBC Melanoma Breast Murine

cancer sarcoma
24
In vitro
2. In vitro
25
SASP-siSTAT3 has an
antitumoral action
What about the immunosuppression ?
SASP-siSTAT3 should boost the immune

response
26
In vivo study
27
3. In vivo
4T1/B16 cells
TNBC or melanoma cells
TNBC Mouse Model
28
3. In vivo
Control siSTAT3
29
3. In vivo
10 days
Study of the immune
and tumor response
30
In vivo
3. In vivo
31
3. In vivo
Increased percentage of T CD4 +

in tumor and spleen
32
These data suggest that SASP-siStat3

immunotherapy has an antitumoral potential and
activate LT CD4 and NK cells à Enhanced
activation of LT CD8 to achieve tumor clearance
Future clincal use ?

33
Perspective
The immunotherapy generated from melanoma

cells works on TNBC cells
à Generate an universal immunotherapy that work

on all STAT3 dependent cells ?
34
Perspectives on STAT3 research in TNBC
35
Perspectives on STAT3 research : Combined therapies
36
STAT3 promotes tumor Generate a STAT3
proliferation and inhibitor is a challenge
immunosuppression and only a few are
approved
TAKE HOME MESSAGE
Lot of perspectives Combined therapies

on STAT3 in seem to be the most
immunotherapy efficient
37
Questions ?

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Présentation 2

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STAT3 as a target in

Cell proliferation Apoptosis

STAT3 is deregulated in many cancers

STAT3 is a very interesting target for immunotherapy

What are the constituents of the Tumor Microenvironment ?

STAT3 overexpressed in tumor cells, tumor-infiltrating

STAT3 modulates the microenvironment

STAT3 induces immunosuppression – HOW ?

o Promote expression of immunosuppressive factors (Il6, Il10)

o Reduces mechanism of antigen presentation,

o Inhibit innate and adaptative immune responses in tumor-infiltrating immune

1) Target molecules upstream

2) Target STAT3 itself

• Pyriméthamine (CLL chronic lymphoid

o Most aggressive and mortal subtype of breast cancer

o 15% of breast cancers

o Lack of expression of estrogen receptor (ER), progesterone receptor (PR),

and human epidermal growth factor receptor 2 (HER2)

o Current treatment = chemotherapy

Urgent need for biomarkers and novel targets

o Lack of molecular targets in TNBC

o Toxicity of indirect STAT3 inhibitors

o Generate a direct STAT3 inhibitor is a big challenge

STAT3 oncogene is overexpressed and constitutively activated in

Pivotal role of STAT3 in the initiation,

1. Inhibition of STAT3 in cancer cells where STAT3 is

TNBC Melanoma Breast Murine

What about the immunosuppression ?

SASP-siSTAT3 should boost the immune

TNBC Mouse Model

Increased percentage of T CD4 +

These data suggest that SASP-siStat3

Future clincal use ?

The immunotherapy generated from melanoma

à Generate an universal immunotherapy that work

TAKE HOME MESSAGE

Lot of perspectives Combined therapies

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