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STATs in cancer inflammation and immunity: a leading role for STAT3

Key Points

  • Signal transducer and activator of transcription (STAT) proteins have dual roles: they transduce signals through the cytoplasm and function as transcription factors in the nucleus. Although some STAT proteins such as STAT1 increase anti-tumour immunity, STAT3 and others induce cancer-promoting inflammation.

  • STAT3 signalling is a major intrinsic pathway for cancer inflammation owing to its frequent activation in malignant cells and key role in regulating many genes crucial for cancer inflammation in the tumour microenvironment.

  • Persistent activation of STAT3, and to a lesser extent STAT5, in diverse human cancers increases proliferation, survival, angiogenesis and metastasis, while also inhibiting anti-tumour immunity.

  • Many STAT3-regulated genes encode cytokines and growth factors, the receptors of which in turn activate the same STAT3 pathways, thereby propagating a stable feedforward loop between tumour cells and non-transformed stromal cells, including myeloid cells and T cells, promoting inflammatory responses that further support tumour growth and survival.

  • Interleukin-6 (IL-6)–Janus kinase (JAK)–STAT3 signalling is important for cancers resulting from the activation of the intrinsic inflammatory pathway owing to genetic or epigenetic changes in tumour cells. Extrinsic environmental inflammatory factors such as sunlight, pathogens and chemical carcinogens can also activate STAT3 through different mechanisms.

  • STAT3 interacts with nuclear factor-κB (NF-κB) at multiple levels and is activated by several NF-κB-regulated gene products, including IL-6. These two transcription factors regulate a multitude of genes important for STAT3 activation and cancer-promoting inflammation.

  • STAT1-driven anti-tumour immune responses and STAT3-mediated immune modulatory pathways can be mutually antagonistic, suggesting that therapeutic interventions targeting specific STATs can tip this balance to convert tumour-promoting inflammation to anti-tumour immune responses. Therefore, STAT3 has emerged as a crucial target for cancer therapy and STAT3 inhibitors are actively being developed.

  • Several tyrosine kinase inhibitors already in the clinic reduce STAT3 signalling by various mechanisms, thereby inducing tumour cell apoptosis and modulating inflammation in the tumour microenvironment in favour of therapeutic responses.

Abstract

Commensurate with their roles in regulating cytokine-dependent inflammation and immunity, signal transducer and activator of transcription (STAT) proteins are central in determining whether immune responses in the tumour microenvironment promote or inhibit cancer. Persistently activated STAT3 and, to some extent, STAT5 increase tumour cell proliferation, survival and invasion while suppressing anti-tumour immunity. The persistent activation of STAT3 also mediates tumour-promoting inflammation. STAT3 has this dual role in tumour inflammation and immunity by promoting pro-oncogenic inflammatory pathways, including nuclear factor-κB (NF-κB) and interleukin-6 (IL-6)–GP130–Janus kinase (JAK) pathways, and by opposing STAT1- and NF-κB-mediated T helper 1 anti-tumour immune responses. Consequently, STAT3 is a promising target to redirect inflammation for cancer therapy.

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Figure 1: STAT3 connects inflammation and cancer.
Figure 2: Different STAT proteins modulate pro-cancer and anti-tumour responses by myeloid cells.
Figure 3: STAT proteins regulate cancer adaptive immunity.
Figure 4: Multilevel interactions between STAT3 and NF-κB.

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Acknowledgements

We would like to thank members of our laboratories who have made major discoveries in the topics discussed here. We also thank the many laboratories that have contributed important publications relevant to the topics in this Review but which could not be cited owing to space limitations. Special thanks go to L. Wang and J. Deng for helping to prepare the figures and references, R. Buettner for compiling data on STAT3 inhibitors, and M. Kortylewski for critical reading of the manuscript.

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Glossary

TH1

A TH1 response is mediated by CD4+ T cells and promoted by type 1 interferons and IL-12, this response mediates its effect through cytokines, particularly IFNγ, promoting cellular immune responses against intracellular infections and tumours.

Innate immune cells

Innate immune cells include natural killer cells, macrophages, neutrophils and dendritic cells, which provide immediate non-specific defence against pathogens. These cells identify and destroy virus-, bacteria- and fungus-infected cells and malignant cells.

Myeloid-derived suppressor cells

MDSCs. Heterogenous and plastic cells. When isolated from normal bone marrow, they do not exhibit imunosuppresive effects. However, when exposed to the tumour microenvironment, they inhibit both CD4+ and CD8+ T cells.

TH17 T cells

Defined by the secretion of IL-17A but not IFNγ or IL-4. TH17 cells have been implicated in protective immunity to intestinal and pulmonary bacterial infections, as well as pathological immunity in several autoimmune diseases.

Type 1 IFNs

Include multiple family members of the IFNα group and the related IFNβ. All type 1 IFNs bind to a single receptor, termed the type 1 or IFNα receptor. They mediate direct anti-viral activity against infected cells, and can also inhibit tumour growth and promote anti-tumour immune responses.

Natural killer cell

A type of lymphocyte that protects against infectious microbes and kills tumour cells through the recognition of specific cell membrane molecules that are upregulated under conditions of cell stress, such as infection or carcinogenic transformation.

Adaptive immunity

Mediated by antigen-specific T lymphocytes and antibodies produced by B cells. It takes longer to develop than innate immunity but has greater antigen specificity and includes the development of immunological memory.

Dendritic cells

Specialized and the most efficient antigen-presenting cells, which can activate T cells and thereby induce antigen-specific immune responses.

CD8+ T cell

The T cell subset from which cytolytic T cells develop. These in turn directly recognize target cells based on the surface expression of antigenic peptide complexed with MHC I molecules and kill their targets by injecting granzymes that induce apoptosis.

Lamina propria

A constituent of the moist linings of mucous membranes, which line different tubes of the body, including the gastrointestinal tract.

Hyper-IgE syndrome

A rare immune and connective tissue disorder characterized by dermatitis, cyst-forming pneumonia and increased serum levels of immunoglobulin E antibody. In some patients it is caused by autosomal dominant STAT3 mutations.

Decoy DNA-binding sites

DNA oligonucleotides with sequence-specific binding sites that sequester their cognate binding proteins, thereby preventing them from binding to the regulatory sequences of nuclear genes.

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Yu, H., Pardoll, D. & Jove, R. STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 9, 798–809 (2009). https://doi.org/10.1038/nrc2734

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