Cutaneous Tumors Cease CXCL9/Mig Production as a Result of IFN-γ–Mediated Immunoediting

Petro, Marianne; Kish, Danielle D.; Guryanova, Olga A.; Ilyinskaya, G. V.; Kondratova, Anna A.; Fairchild, Robert L.; Gorbachev, Anton V.

doi:10.4049/jimmunol.1201906

Cited by 19 publications

(20 citation statements)

References 36 publications

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“…38,39 Recently, Cxcl9 2/2 mice were reported to form large tumors due to immunosurveillance escape. 28 Thus our findings indicate that STAT2 orchestrates the expression of genes that are important in the differentiation and recruitment of immune effector cells to the tumor site.…”

Section: Discussionmentioning

confidence: 64%

“…Bone marrow cells were differentiated into DCs with complete IMDM medium (Iscove's DMEM supplemented with 10% FBS, penicillin/streptomycin, gentamicin, and b-ME) enriched with 3.3 ng mL 21 of GM-CSF (BD Biosciences). 23 At day 6, resting DC cultures were stimulated with 100 ng mL 21 of LPS 3755 (Sigma-Aldrich), and pulsed with 5 lg mL 21 of human peptide gp100 [25][26][27][28][29][30][31][32][33] (GenScript, Piscataway, NJ) for 2 hr at 37 C.…”

Section: Generation Of Bone Marrow-derived Dendritic Cells (Bmdcs)mentioning

confidence: 99%

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Host STAT2/type I interferon axis controls tumor growth

Yue

Estioko

et al. 2014

Int. J. Cancer

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The role of STAT2 in mediating the antigrowth effects of type I interferon (IFN) is well-documented in vitro. Yet evidence of IFN-activated STAT2 as having tumor suppressor function in vivo and participation in antitumor immunity is lacking. Here we show in a syngeneic tumor transplantation model that STAT2 reduces tumor growth. Stat2−/− mice formed larger tumors compared to wild type (WT) mice. IFN-β treatment of Stat2−/− mice did not cause tumor regression. Gene expression analysis revealed a small subset of immunomodulatory genes to be downregulated in tumors established in Stat2−/− mice. Additionally, we found tumor antigen cross-presentation by Stat2−/− dendritic cells to T cells to be impaired. Adoptive transfer of tumor antigen specific CD8+ T cells primed by Stat2−/− dendritic cells into tumor-bearing Stat2−/− mice did not induce tumor regression with IFN-β intervention. We observed that an increase in the number of CD4+ and CD8+ T cells in the draining lymph nodes of IFN-β-treated tumor-bearing WT mice was absent in IFN-β treated Stat2−/− mice. Thus our study provides evidence for further evaluation of STAT2 function in cancer patients receiving type I IFN based immunotherapy.

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Section: Discussionmentioning

confidence: 64%

Section: Generation Of Bone Marrow-derived Dendritic Cells (Bmdcs)mentioning

confidence: 99%

Host STAT2/type I interferon axis controls tumor growth

Yue

Estioko

et al. 2014

Int. J. Cancer

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“…A recent study has demonstrated that cutaneous melanomas decrease CXCL9 production as a consequence of immune editing and selection of CXCL9-deficient clones (37). We have not excluded the possibility of immune editing in the metastatic-like model; however, the maintenance of Ifnγ, Cxcl9 , and Cxcl10 expression in late-stage metastases following aminophylline treatment argues against the selection and predominance of loss-of-function clones in our model.…”

Section: Discussionmentioning

confidence: 99%

Melanoma Induces, and Adenosine Suppresses, CXCR3-Cognate Chemokine Production and T-cell Infiltration of Lungs Bearing Metastatic-like Disease

Clancy‐Thompson

Perekslis

Croteau

et al. 2015

Cancer Immunology Research

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Despite immunogenicity, melanoma-specific vaccines have demonstrated minimal clinical efficacy in patients with established disease but enhance survival when administered in the adjuvant setting. Therefore, we hypothesized that organs bearing metastatic-like melanoma may differentially produce T-cell chemotactic proteins over the course of tumor development. Using an established model of metastatic-like melanoma in lungs, we assessed the production of specific cytokines and chemokines over a time-course of tumor growth, and we correlated chemokine production with chemokine receptor-specific T-cell infiltration. We observed that the interferon (IFN)-inducible CXCR3-cognate chemokines (CXCL9 and CXCL10) were significantly increased in lungs bearing minimal metastatic lesions, but chemokine production was at or below basal levels in lungs with substantial disease. Chemokine production correlated with infiltration of the organ compartment by adoptively transferred CD8+ tumor antigen-specific T cells in a CXCR3- and host IFNγ-dependent manner. Adenosine signaling in the tumor microenvironment suppressed chemokine production and T-cell infiltration in the advanced metastatic lesions, and this suppression could be partially reversed by administration of the adenosine receptor antagonist aminophylline. Collectively, our data demonstrate that CXCR3-cognate ligand expression is required for efficient T cell access of tumor-infiltrated lungs, and these ligands are expressed in a temporally restricted pattern that is governed, in part, by adenosine. Therefore, pharmacologic modulation of adenosine activity in the tumor microenvironment could impart therapeutic efficacy to immunogenic but clinically ineffective vaccine platforms.

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“…As IFN-g has been demonstrated to have a profound effect in the immune system (25,26), both innate and adaptive immunity, …”

Section: Discussionmentioning

confidence: 99%

IFN-γ Primes Macrophage Activation by Increasing Phosphatase and Tensin Homolog via Downregulation of miR-3473b

Xue

Wang

et al. 2014

The Journal of Immunology

112

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The classical activation of macrophages, one of major innate effector cells, requires IFN-γ pretreatment (priming) and subsequent TLR stimuli (triggering). The priming effect of IFN-γ can promote macrophages to secrete higher level of proinflammatory cytokines but lower level of the anti-inflammatory cytokines, enhancing microbicidal and tumoricidal activity of macrophages. However, the underlying molecular mechanisms for IFN-γ–priming effect on macrophage activation remain to be fully understood. microRNAs (miRNAs) are now emerging as important regulators in immune response, including signaling transduction in immune cell function. In this study, we explored the effect of IFN-γ on miRNA expression profiling in macrophages and tried to identify the definite miRNA involved in the priming effect of IFN-γ. We discovered that miR-3473b, which was significantly downregulated after IFN-γ priming, could attenuate the priming effect of IFN-γ. miR-3473b promoted Akt/glycogen synthase kinase 3 signaling and IL-10 production through directly targeting phosphatase and tensin homolog (PTEN) to suppress activation of macrophages and inflammatory response. Our data indicate that IFN-γ beefs up macrophage innate response and cytotoxicity by downregulating miR-3473b to release PTEN from suppression, and then the increase of PTEN contributes to the full activation of IFN-γ–primed macrophages. Our results provide mechanistic insight to priming effect of IFN-γ on macrophage classical activation by identifying an IFN-γ/miR-3473b/PTEN regulatory loop in the regulation of macrophage function.

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Cutaneous Tumors Cease CXCL9/Mig Production as a Result of IFN-γ–Mediated Immunoediting

Cited by 19 publications

References 36 publications

Host STAT2/type I interferon axis controls tumor growth

Host STAT2/type I interferon axis controls tumor growth

Melanoma Induces, and Adenosine Suppresses, CXCR3-Cognate Chemokine Production and T-cell Infiltration of Lungs Bearing Metastatic-like Disease

IFN-γ Primes Macrophage Activation by Increasing Phosphatase and Tensin Homolog via Downregulation of miR-3473b

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