STAT3 and the Immune System

Maureen Sherry Lynes

February 29, 2012

Overview

STAT family; STAT3 signaling and structure

Role of STAT3 revealed by tissue specific knockouts

STAT3 and the anti-tumor immune response

Therapeutic approaches for targeting STAT3

Paper discussion

The STAT Family of Transcription Factors

7 mammalian STAT proteins

latent cytoplasmic transcription factors

Important in a wide range of physiological processes

STAT1 Impaired interferon response; increased susceptibility to tumorsSTAT2 Impaired interferon responseSTAT3 Embryonic lethalSTAT4 Impaired Th1 differentiation due to loss of Il-12 responsivenessSTAT5A Impaired mammary gland development (decreased prolactin response)STAT5B Impaired growth (growth hormone signaling impaired)STAT6 Impaired Th1 differentiation due to loss of Il-4 responsiveness

Adapted from Darnell and Levy, 2002

How is the STAT3 pathway activated?

•Cytokines, growth factors

•Secreted by diverse cell types in response to diverse processes

•Receptor specific

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Minegishi et al 2011

The STAT3 Signaling Pathway

Negative Regulation of STAT3 signaling

1. Cytoplasmic phosphatases

2. SOCs proteins

3. Pias Proteins

4. STAT3ß

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Figure 1.2. Domain structure of the STAT proteins.

Domain Structure of STAT3

STAT3 Target Genes

STAT3

Immortalization (hTERT)

Apoptosis (Survivin, bcl-xl)

Growth (C-myc, cyclin D)

Angiogenesis (VEGF)

Differentiation

Tissue Specific STAT3 Knockouts

•Brain: obesity, inability to control temperature, diabetes

•Skin: impaired wound healing, resistance to skin cancer

•Mouse Embryonic Stem Cells: loss of pluripotency

•Lung

•Macrophages and Neutrophils

•Liver

•Th17 development

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Gao et al, 2004.

STAT3 and the Acute Phase Response

•Liver: site of integration of signals from tissue, toxins and bacterial products in blood, etc

• Macrophages in the periphery: cytokine release

•Hepatocytes respond to cytokines (IL-6, IL-1 for example) and upregulate appropriate response proteins (clotting, innate responses to bacterial infection, toxins, etc)

•Hepatocyte deletion of STAT3- polymicrobial sepsis

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Similar bacterial load; decreased acute phase proteins, increased inflammatory cytokines such as IL-6 and TNFa

LPS injection or cecal ligation and puncture:

Sakamori et al 2007

STAT3 in macrophages and neutrophils

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Takeda et al, 1999.

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•STAT3 deleted in cells expressing lysozyme M

•Mice were susceptible to LPS-induced endotoxic shock

•Macrophages constitutively activated

STAT3 in macrophages and neutrophils

•STAT3 -/- macrophages are resistant to IL-10

•IL-10 normally dampens macrophage activation and response

•LysmCre STAT3 mice develop chronic enterocholitis

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STAT3 in the lung epithelium

• House dustmite extract: induces allergic inflammation in the lung, as well as STAT3 activation

•Lung specific STAT3 KO: appears normal

•STAT3 lung KO: decreased airway hyperresponsiveness, immune infiltration upon HDM challenge

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Simeone et al, 2007.

STAT3 in Th17 Differentiation

•CD4+, defense against extracellular bacteria, fungi

•Pathogenic autoimmune responses

•Celiac, IBD, etc QuickTime™ and a

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Fischer 2008

STAT3 in hyper IgE syndrome

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activation

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DNA binding

STAT3 in hyper IgE syndrome

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Recurrent skin and lung infections (Th17, lung epithelial defects?)

Activation, Duration, and extent of STAT3 signaling is tightly regulated

•Brain: obsesity, inability to control temperature, diabetes

•Skin: impaired wound healing, resistance to skin cancer

•Mouse Embryonic Stem Cells: loss of pluripotency

•Lung- promotes allergic inflammation

•Macrophages and Neutrophils- prevents constitutve activation,

•Liver: actue phase response; integration of signals from tissues

•Th17 differentiation

Gao et al, 2004.

STAT3 is constitutively activated in many human cancers

Inappropriately activated or overexpressed

Prevents apoptosis, stimulates migration, stimulates proliferation, increases angiogenesis

Upregulates cytokines that perpetuate STAT3 activation in the tumor and surrounding tissue

STAT3 and tumorigenesis

Wang, Rich et al. Stem Cells 2009

DN STAT3 induces melanoma regression in a mouse model

Transfection of B16 tumors with dominant negative STAT3 induces tumor regression

Bystander effect: regression disproportionate to transfection

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Niu et al Cancer Research 1999

STAT3 Suppresses Anti-Tumor Immunity

Cultured B16 cells transfected with DN STAT3: increased production of pro-inflammatory cytokines and chemokines (TNFa, RANTES, IP-10)

In vivo: enhances macrophage and neutrophil infiltration

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Wang et al Nature Med 2004

STAT3 Suppresses Anti-Tumor Immunity

Yu et al Nature Reviews 2007

STAT3 as a therapeutic target

STAT3 as a therapeutic target

Activation

EGFR antibodies; small molecules

Jak inhibitors

Multi-receptor kinase inhibitors

Protein-protein interactions

Small molecules to prevent dimerization

phosphoTyr peptides

DNA binding

Double stranded oligonucleotides

Nuclear translocation, natural inhibitors

Summary

STAT3 is a cytokine and growth factor activated transcription factor

STAT3 has a wide range of functions, both anti and pro inflammatory depending on the tissue and physiological context

STAT3 is also involved in disease states, such as asthma, colitis, and cancer

STAT3 can suppress anti-tumor immunity

STAT3 directed therapeutics is an active area of research

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