Many oncogenic signalling pathways converge on signal transducer and activator of transcription 3 (STAT3). As a result, STAT3 is constitutively activated in a range of cancers.
STAT3 is a broad transcriptional regulator, and constitutively active STAT3 leads to a gene-expression pattern that promotes tumour-cell survival and proliferation, tumour angiogenesis and metastasis.
STAT3 provides the first direct link between oncogenesis and immune evasion. STAT3 activity inhibits the expression of T helper 1 (TH1)-type immunostimulating molecules while promoting the expression of immunosuppressive factors.
STAT3 activity propagates from tumour cells to immune cells in the tumour microenvironment, thereby mediating immune evasion by blocking both the production and sensing of inflammatory signals by various components of the immune system.
The propagation of STAT3 activity from tumour cells to diverse immune cells, and from one immune cell type to another, and back to tumour cells, is accomplished by STAT3-regulated factors, such as interleukin-10 and vascular endothelial growth factor, that are also STAT3 activators.
Targeting STAT3 in either tumour cells or immune cells stimulates both innate and adaptive immune responses against the tumour.
Combining STAT3 targeting with other promising immunotherapeutic approach(es) is anticipated to generate optimal anti-tumour immune responses.
Immune cells in the tumour microenvironment not only fail to mount an effective anti-tumour immune response, but also interact intimately with the transformed cells to promote oncogenesis actively. Signal transducer and activator of transcription 3 (STAT3), which is a point of convergence for numerous oncogenic signalling pathways, is constitutively activated both in tumour cells and in immune cells in the tumour microenvironment. Constitutively activated STAT3 inhibits the expression of mediators necessary for immune activation against tumour cells. Furthermore, STAT3 activity promotes the production of immunosuppressive factors that activate STAT3 in diverse immune-cell subsets, altering gene-expression programmes and, thereby, restraining anti-tumour immune responses. As such, STAT3 propagates several levels of crosstalk between tumour cells and their immunological microenvironment, leading to tumour-induced immunosuppression. Consequently, STAT3 has emerged as a promising target for cancer immunotherapy.
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We would like to thank members of our laboratory, especially G.-L. Niu, M. Kujawski, T.-H. Wang and L. Burdelya, for their contributions to the work summarized here. We would also like to acknowledge the pioneering work of R. Jove in linking STAT3 with cancer that inspired the initial gene-therapy experiment. H.Y. was supported by US National Institutes of Health (NIH) grants and by the Dr Tsai-fan Yu Cancer Research Endowment. D.P. was supported by NIH grants and gifts from the Topercer family, D. Needle, J. Goldsmith, the Seraph Foundation and the Janney Fund.
The authors declare no competing financial interests.
- Danger signals
A danger signal is normally defined as the pathogen-associated molecular pattern that is recognized by host receptors. Danger signals often trigger the production of cytokines, chemokines and other physiological mediators, such as nitric oxide, leading to immune responses against the pathogen. In the context of this Review, 'danger signals' refer to the similar cytokines, chemokines and other T helper 1-type immunostimulating molecules that are produced by transformed cells on STAT3 inhibition.
- Tolerogenic dendritic cells
Dendritic cells that can attenuate T-cell-mediated immune responses by anergizing or changing the effector function of antigen-specific T cells.
- Mx1–Cre–loxP system
The Mx1–Cre–loxP system allows specific gene ablation, mostly in the haematopoietic cell lineages of adult mice. Injection of polyinosinic–polycytidylic-acid oligonucleotides stimulates the production of type-I interferons, which induce Cre recombinase expression through the interferon-sensitive Mx1 promoter, resulting in the ablation of target gene alleles flanked by loxP sites.
- T-cell anergy
A state of T-cell unresponsiveness to stimulation with antigen. It can be induced by stimulation with a large amount of specific antigen in the absence of the engagement of co-stimulatory molecules.
- Regulatory T (TReg) cells
A rare population of CD4+ T cells that naturally express high levels of CD25 (the interleukin-2 receptor α-chain) and the transcription factor forkhead box P3 (FOXP3), and that have suppressive regulatory activity towards effector T cells and other immune cells. Absence or dysfunction of TReg cells is associated with severe autoimmunity. In tumours, TReg cells are induced and proliferate, thereby suppressing anti-tumour immunity.
- Plasmacytoid dendritic cells
A subset of dendritic cells (DCs) that are described as plasmacytoid because of their microscopic appearance that resembles plasmablasts. In humans, these DCs can be derived from lineage-negative stem cells in peripheral blood and are the main producers of type-I interferon (IFN) in response to virus infections. Recent studies have identified a subset of type-I IFN-producing DCs in mice, which are characterized by expression of B220 and Ly6C.
- Nucleophosmin/anaplastic lymphoma kinase (NPM/ALK) oncoprotein
An oncogenic fusion tyrosine kinase that is associated with a specific type of non-Hodgkin's lymphoma. The translocation between chromosomes 5 and 2 results in fusion of the amino-terminal part of the ubiquitous nucleolar protein NPM to the cytoplasmic fragment of the receptor tyrosine kinase ALK, creating a hybrid tyrosine kinase with constitutive activity.
- Immune-mediated colitis
An inflammatory disease of the colon most commonly classified as ulcerative colitis or Crohn's disease. Various hereditary and induced mouse models of human colitis have been developed.
- RNA interference
(RNAi). Double-stranded RNAs (dsRNAs) with sequences that precisely match a given gene are able to 'knock down' the expression of that gene by directing RNA-degrading enzymes to destroy the encoded mRNA transcript. The two most common forms of dsRNAs used for gene silencing are short — usually 21-bp long — small interfering RNAs (siRNAs) or the plasmid-delivered short hairpin RNAs (shRNAs).
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Yu, H., Kortylewski, M. & Pardoll, D. Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment. Nat Rev Immunol 7, 41–51 (2007). https://doi.org/10.1038/nri1995
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