Role of Stat3 in suppressing anti-tumor immunity

Kortylewski, Marcin; Yu, Hua

doi:10.1016/j.coi.2008.03.010

Cited by 166 publications

(126 citation statements)

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“…These approaches, which include in vivo blocking of Stat3 by using genetic deletions in tumor cells or in tumor-infiltrating immune cells or by administration of pharmacological inhibitors, have variable rates of success in stimulating antitumor immune responses (5,27,40,41); however, both of these approaches have limited clinical application until targetspecific delivery is possible. To our knowledge, our study provides the first report of the use of ex vivo Stat3-inactivated tumor cells as an immunotherapy; this approach has the advantage of immunizing the host with the whole array of Ags expressed by the tumor cells in a stimulatory microenvironment composed of multiple proinflammatory cytokines and chemokines to generate an antitumor immune response.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, Stat3 has recently been shown to mediate tumor-induced immunosuppression at many levels (3,4). Stat3 activation in tumor cells not only inhibits the production of immunostimulatory mediators but also promotes the secretion of immunosuppressive factors that, in turn, activate Stat3 in tumorinteracting cells (5). This feed-forward mechanism leads to tumor immune evasion through the suppression of innate and adaptive antitumor immune responses (6).…”

mentioning

confidence: 99%

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Targeting Stat3 Induces Senescence in Tumor Cells and Elicits Prophylactic and Therapeutic Immune Responses against Breast Cancer Growth Mediated by NK Cells and CD4+ T Cells

Tkach

Coria

Rosemblit

et al. 2012

The Journal of Immunology

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Aberrant Stat3 activation and signaling contribute to malignant transformation by promoting cell cycle progression, inhibiting apoptosis, and mediating tumor immune evasion. Stat3 inhibition in tumor cells induces the expression of chemokines and proinflammatory cytokines, so we proposed to apply Stat3-inhibited breast cancer cells as a source of immunogens to induce an antitumor immune response. Studies were performed in two murine breast cancer models in which Stat3 is activated: progestin-dependent C4HD cells and 4T1 cells. We immunized BALB/c mice with irradiated cancer cells previously transfected with a dominant-negative Stat3 vector (Stat3Y705F) in either a prophylactic or a therapeutic manner. Prophylactic administration of breast cancer cells transfected with Stat3Y705F (Stat3Y705F-breast cancer cells) inhibited primary tumor growth compared with administration of empty vector-transfected cells in both models. In the 4T1 model, 50% of the challenged mice were tumor free, and the incidence of metastasis decreased by 90%. In vivo assays of C4HD tumors showed that the antitumor immune response involves the participation of CD4+ T cells and cytotoxic NK cells. Therapeutic immunization with Stat3Y705F-breast cancer cells inhibited tumor growth, promoted tumor cell differentiation, and decreased metastasis. Furthermore, inhibition of Stat3 activation in breast cancer cells induced cellular senescence, contributing to their immunogenic phenotype. In this work, we provide preclinical proof of concept that ablating Stat3 signaling in breast cancer cells results in an effective immunotherapy against breast cancer growth and metastasis. Moreover, our findings showing that Stat3 inactivation results in induction of a cellular senescence program disclose a potential mechanism for immunotherapy research.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Targeting Stat3 Induces Senescence in Tumor Cells and Elicits Prophylactic and Therapeutic Immune Responses against Breast Cancer Growth Mediated by NK Cells and CD4+ T Cells

Tkach

Coria

Rosemblit

et al. 2012

The Journal of Immunology

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“…13,49 Such cancer cell STAT3-mediated inflammation was observed in the DEN-induced liver tumor model. As shown in Figure 2C, expression of CCR2, F4/80, TNF-␣, IFN-␥, and TGF-␤ was only slightly elevated in the nontumor tissues of wildtype mice, confirming a lack of overt injury and inflammation in this model.…”

Section: Stat3 and Inflammation In The Den And CCL 4 Modelsmentioning

confidence: 99%

Hepatoprotective versus Oncogenic Functions of STAT3 in Liver Tumorigenesis

Wang

Lafdil

Wang

et al. 2011

The American Journal of Pathology

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Aberrantly hyperactivated STAT3 has been found in human liver cancers as an oncogene; however, STAT3 has also been shown to exert hepatoprotective effects during liver injury. The balancing act that STAT3 plays between hepatoprotection and liver tumorigenesis remains poorly defined. In this study, the diethylnitrosamine (DEN)-induced liver tumor model and the chronic carbon tetrachloride (CCl 4 )-induced liver fibrosis model were both used to investigate the role of STAT3 in liver tumorigenesis. Hepatocyte-specific STAT3 knockout mice were resistant to liver tumorigenesis induced by a single DEN injection, whose tumorigenesis was associated with minimal chronic liver inflammation, injury, and fibrosis. In contrast, long-term CCl 4 treatment resulted in severe hepatic oxidative damage, inflammation, and fibrosis but rarely induced liver tumor formation in wild-type mice. Despite the oncogenic function of STAT3 in DEN-induced liver tumor, hepatocyte-specific STAT3 knockout mice were more susceptible to liver tumorigenesis after 16 weeks of CCl 4 injection, which was associated with higher levels of liver injury, inflammation, fibrosis, and oxidative DNA damage compared with wild-type mice. These findings suggest that the hepatoprotective feature of STAT3 prevents hepatic damage and fibrosis under the condition of persistent inflammatory stress, consequently suppressing injurydriven liver tumor initiation. Once liver tumor cells have developed, STAT3 likely acts as an oncogenic factor to promote tumor growth.

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“…Le facteur de transcription STAT3 (signal transducer and activator of transcription 3) est fréquemment activé dans les cancers via l'activation constitutive de récep-teurs à activité tyrosine-kinase et de kinases telles que Src [5]. Dans les cellules tumorales, STAT3 exerce des l'oxygène (mutations des gènes VHL, Raf, Ras, BRAf) [3] (Figure 1).…”

Section: Activation De Stat3 Dans Les Cellules Tumoralesunclassified

“…L'hypoxie tumorale semble ainsi jouer un rôle central dans les mécanismes d'échappement tumoral au système immunitaire. fonctions anti-apoptotiques et promeut la prolifération cellulaire et la résistance aux thérapies anticancéreuses, dont l'immunothéra-pie [5]. En effet, STAT3, d'une part, inhibe l'expression de cytokines immunostimulatrices et augmente l'expression de cytokines immunosuppressives par les cellules tumorales et, d'autre part, altère les fonctions immunoactivatrices des cellules présentatrices d'antigènes, comme les macrophages et les cellules dendritiques [7].…”

Section: Activation De Stat3 Dans Les Cellules Tumoralesunclassified