STAT1 and STAT3 in tumorigenesis

Avalle, Lidia; Pensa, Sara; Regis, Gabriella; Novelli, Francesco; Poli, Valeria

doi:10.4161/jkst.20045

Cited by 219 publications

(217 citation statements)

References 77 publications

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“…65 The binding ratio of different STAT members to the same STAT sites can affect gene expression and cell differentiation dramatically. [66][67][68] In our study, we found IL-15 stimulation dramatically activated STAT5 signaling and induced more pSTAT5 binding to the nine STAT sites on the promoter of ATM, 53BP1, MDC1 DNA damage genes. As a consequence of this binding, there are less pSTAT3, more transcriptionally repressive histones (H3K27) and less transcriptionally active histones (H3K4, P300, Acy 300) binding to the promoters.…”

Section: Discussionsupporting

confidence: 52%

IL-15 enhances the antitumor effect of human antigen-specific CD8⁺T cells by cellular senescence delay

et al. 2016

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Optimal expansion protocols for adoptive human T-cell therapy often include interleukin (IL)-15; however, the mechanism by which IL-15 improves the in vivo antitumor effect of T cells remains to be elucidated. Using human T cells generated from HLA-A2+ donors against novel T-cell epitopes derived from the human U266 myeloma cell line Ig light chain V-region (idiotype) as a model, we found that T cells cultured with IL-15 provided superior resistance to tumor growth in vivo, compared with IL-2, after adoptive transfer into immunodeficient hosts. This effect of IL-15 was associated with delayed/reversed senescence in tumor antigen-specific memory CD8 C T cells mediated through downregulation of P21 WAF1 , P16 INK4a , and P53 expression. Compared to IL-2, IL-15 stimulation dramatically activated JAK3-STAT5 signaling and inhibited the expression of DNA damage genes. Thus, our study elucidates a new mechanism for IL-15 in the regulation of STAT signaling pathways and CD8 C T-cell senescence.

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Section: Discussionsupporting

confidence: 52%

IL-15 enhances the antitumor effect of human antigen-specific CD8⁺T cells by cellular senescence delay

et al. 2016

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“…STAT3 activation is enhanced in STAT1-null cells, and conversely, STAT1 activation is enhanced in STAT3-null cells. 16,[60][61][62][63] Although our studies did not show a difference in STAT3 phosphorylation during re-stimulation in a Tc1 environment, STAT1 phosphorylation was significantly altered. As STAT3 and STAT1 have different functions and even oppose each other, their ratio determines the Tc17 cell phenotype.…”

Section: Discussioncontrasting

confidence: 77%

The differentiation and plasticity of Tc17 cells are regulated by CTLA-4-mediated effects on STATs

et al. 2017

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As the blockade of inhibitory surface-molecules such as CTLA-4 on T cells has led to recent advances in antitumor immune therapy, there is great interest in identifying novel mechanisms of action of CD8 C T cells to evoke effective cytotoxic antitumor responses. Using in vitro and in vivo models, we investigated the molecular pathways underlying the CTLA-4-mediated differentiation of IL-17-producing CD8 C T cells (Tc17 cells) that strongly impairs cytotoxicity. Our studies demonstrate that Tc17 cells lacking CTLA-4 signaling have limited production of STAT3-target gene products such as IL-17, IL-21, IL-23R and RORgt. Upon re-stimulation with IL-12, these cells display fast downregulation of Tc17 hallmarks and acquire Tc1 characteristics such as IFNg and TNF-a co-expression, which is known to correlate with tumor control. Indeed, upon adoptive transfer, these cells were highly efficient in the antigen-specific rejection of established OVA-expressing B16 melanoma in vivo. Mechanistically, in primary and re-stimulated Tc17 cells, STAT3 binding to the IL-17 promoter was strongly augmented by CTLA-4, associated with less binding of STAT5 and reduced relative activation of STAT1 which is known to block STAT3 activity. Inhibiting CTLA-4-induced STAT3 activity reverses enhancement of signature Tc17 gene products, rendering Tc17 cells susceptible to conversion to Tc1-like cells with enhanced cytotoxic potential. Thus, CTLA-4 critically shapes the characteristics of Tc17 cells by regulating relative STAT3 activation, which provides new perspectives to enhance cytotoxicity of antitumor responses.

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“…The JAK2/ STAT3 pathway is also downstream of other receptor tyrosine kinases, including PDGF-R (24), ILR (21,25), and EGF-R (24, 25), which are known to promote tumorigenesis in MPNSTs. STAT3 is considered an oncogene and promotes transcription of genes linked to cancer progression, driving cell migration, invasion, and survival (26). In the ST8814 cells, tyrosine phosphorylation of STAT3 was robustly induced after just 30 minutes of HGF stimulation and maintained throughout the 3-hour time course.…”

Section: Resultsmentioning

confidence: 99%

STAT3 and HIF1α Signaling Drives Oncogenic Cellular Phenotypes in Malignant Peripheral Nerve Sheath Tumors

Rad

Dodd

Thomas

et al. 2015

Molecular Cancer Research

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Therapeutic options are limited for neurofibromatosis type 1 (NF1)-associated malignant peripheral nerve sheath tumors (MPNST) and clinical trials using drug agents have so far been unsuccessful. This lack of clinical success is likely attributed to high levels of intratumoral molecular heterogeneity and variations in signal transduction within MPNSTs. To better explore the variance of malignant signaling properties within heterogeneous MPNSTs, four MPNST cell lines (ST8814, S462, S1844.1, and S1507.2) were used. The data demonstrate that small-molecule inhibition of the MET proto-oncogene and mTOR had variable outcome when preventing wound healing, cell migration, and invasion, with the S462 cells being highly resistant to both. Of interest, targeted inhibition of the STAT3 transcription factor suppressed wound healing, cell migration, invasion, and tumor formation in all four MPNST lines, which demonstrates that unlike MET and mTOR, STAT3 functions as a common driver of tumorigenesis in NF1-MPNSTs. Of clinical importance, STAT3 knockdown was sufficient to block the expression of hypoxiainducible factor (HIF)1a, HIF2a, and VEGF-A in all four MPNST lines. Finally, the data demonstrate that wound healing, cell migration, invasion, and tumor formation through STAT3 are highly dependent on HIF signaling, where knockdown of HIF1a ablated these oncogenic facets of STAT3.Implications: This research reveals that aberrant STAT3 and HIF1a activity drives tumor progression in MPNSTs, indicating that inhibition of the STAT3/HIF1a/VEGF-A signaling axis is a viable treatment strategy.

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STAT1 and STAT3 in tumorigenesis

Abstract: These authors contributed equally to this work.

Cited by 219 publications

References 77 publications

IL-15 enhances the antitumor effect of human antigen-specific CD8⁺T cells by cellular senescence delay

IL-15 enhances the antitumor effect of human antigen-specific CD8⁺T cells by cellular senescence delay

The differentiation and plasticity of Tc17 cells are regulated by CTLA-4-mediated effects on STATs

STAT3 and HIF1α Signaling Drives Oncogenic Cellular Phenotypes in Malignant Peripheral Nerve Sheath Tumors

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STAT1 and STAT3 in tumorigenesis

Abstract: These authors contributed equally to this work.

Cited by 219 publications

References 77 publications

IL-15 enhances the antitumor effect of human antigen-specific CD8+T cells by cellular senescence delay

IL-15 enhances the antitumor effect of human antigen-specific CD8+T cells by cellular senescence delay

The differentiation and plasticity of Tc17 cells are regulated by CTLA-4-mediated effects on STATs

STAT3 and HIF1α Signaling Drives Oncogenic Cellular Phenotypes in Malignant Peripheral Nerve Sheath Tumors

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IL-15 enhances the antitumor effect of human antigen-specific CD8⁺T cells by cellular senescence delay

IL-15 enhances the antitumor effect of human antigen-specific CD8⁺T cells by cellular senescence delay