Article

Interferons, immunity and cancer immunoediting

Department of Pathology and Immunology, Washington University in St. Louis, San Luis, Missouri, United States
Nature reviews. Immunology (Impact Factor: 34.99). 12/2006; 6(11):836-48. DOI: 10.1038/nri1961
Source: PubMed

ABSTRACT

A clear picture of the dynamic relationship between the host immune system and cancer is emerging as the cells and molecules that participate in naturally occurring antitumour immune responses are being identified. The interferons (IFNs) - that is, the type I IFNs (IFNalpha and IFNbeta) and type II IFN (IFNgamma) - have emerged as central coordinators of tumour-immune-system interactions. Indeed, the decade-old finding that IFNgamma has a pivotal role in promoting antitumour responses became the focus for a renewed interest in the largely abandoned concept of cancer immunosurveillance. More recently, type I IFNs have been found to have distinct functions in this process. In this Review, we discuss the roles of the IFNs, not only in cancer immunosurveillance but also in the broader process of cancer immunoediting.

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    • "While immune cells mediate cancer immune surveillance, they also contribute to the formation of tumor microenvironment and promote tumor growth (Grivennikov et al., 2010; Whiteside, 2008). Interferon-g (IFN-g), produced by effector T cells and innate immune cells, is known as a cytokine that promotes innate and adaptive immune responses against microbial infections and tumor development (Dunn et al., 2006). IFN-g regulates the differentiation and effector function of different types of immune cells and also inhibits the growth and survival of cancer cells (Zaidi and Merlino, 2011). "
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    ABSTRACT: USP15 is a deubiquitinase that negatively regulates activation of naive CD4+ T cells and generation of IFN-γ-producing T helper 1 (Th1) cells. USP15 deficiency in mice promotes antitumor T cell responses in a transplantable cancer model; however, it has remained unclear how deregulated T cell activation impacts primary tumor development during the prolonged interplay between tumors and the immune system. Here, we find that the USP15-deficient mice are hypersensitive to methylcholantrene (MCA)-induced fibrosarcomas. Excessive IFN-γ production in USP15-deficient mice promotes expression of the immunosuppressive molecule PD-L1 and the chemokine CXCL12, causing accumulation of T-bet+ regulatory T cells and CD11b+Gr-1+ myeloid-derived suppressor cells at tumor site. Mixed bone marrow adoptive transfer studies further reveals a T cell-intrinsic role for USP15 in regulating IFN-γ production and tumor development. These findings suggest that T cell intrinsic USP15 deficiency causes excessive production of IFN-γ, which promotes an immunosuppressive tumor microenvironment during MCA-induced primary tumorigenesis.
    Full-text · Article · Dec 2015 · Cell Reports
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    • "Among melanoma cell lines, the increments in extracellular levels of KYN that were induced by IFN-γ ranged from 4-to 50-fold. As tumor cells are obligatory targets for IFN-γ (Dunn et al., 2006), the observed differences in KYN abundance may be the result of differences in the expression of IFN-γ receptors (IFNGR 1 and 2) or abnormal JAK1/2 or STAT1 expression between the melanoma cell lines studied. In normal cells, the KYN increment caused by IFN-γ ranged from 25-fold in fibroblasts to 76-fold in melanocytes . "
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    ABSTRACT: A key link between amino acid catabolism and immune regulation in cancer is the augmented trypto-phan (Trp) catabolism through the kynurenine pathway (KP), a metabolic route induced by interferon-γ (IFN-γ) and related to poor prognosis in melanomas. Besides its role in cancer, IFN-γ plays a key role in the control of pigmentation homeostasis. Here we measured KP metabo-lites in human melanoma lines and skin melanocytes and fibroblasts in response to IFN-γ. In general, IFN-γ affected KP in skin cells more than in melanoma cells, supporting IFN-γ roles in skin physiology and that of stromal cells in modulating the tumor microenvironment.
    Full-text · Article · Nov 2015 · Biological Chemistry
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    • "However, the underlying mechanisms responsible for the better outcome of MMR-deficient CRC are poorly understood. A possible hypothesis is that in tumor with MMR defects by T-cells, macrophages, and natural killers, infiltration might be increased enhancing immune surveillance mechanisms[15]. In fact, Sinicrope et al observed that a higher density of tumor infiltrating lymphocytes (TILs), most of which were CD3+T lymphocytes[16], was associated with better disease free survival in cases with defective versus intact MMR[17]. Several studies have investigated T-cell activation in CRC and their influence on tumour behaviour and patient prognosis. "
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    ABSTRACT: Background There is evidence that colorectal cancers (CRC) with DNA mismatch repair deficiency (MMR-D) are associated with a better prognosis than the generality of large bowel malignancies. Since an active immune surveillance process has been demonstrated to influence CRC outcome, we investigated whether MMR-D can enhance the immune response in CRC.Patients and Methods A group of 113 consecutive patients operated for CRC (42 stage I or II and 71 with stage III or IV) was retrospectively analyzed. The expression of MMR genes (MSH2, MLH1, MSH6 and PSM2) and co-stimulatory molecule CD80 was assessed by tissue microarray immunohistochemistry. In addition, tumor infiltrating mononuclear cells (TIMC) and T cell subpopulations (CD4, CD8, T-bet and FoxP-3) were quantified. The effect of specific siRNA (siMSH2, siMLH1, siMSH6 and siPSM2) transfection in HT29 on CD80 expression was quantified by flow cytometry. Non parametric statistics and survival analysis were used.Results Patients with MMR-D showed a higher T-bet/CD4 ratio (p = 0.02), a higher rate of CD80 expression and CD8 lymphocyte infiltration compared to those with no MMR-D. Moreover, in the MMR-D group, the Treg marker FoxP-3 was not expressed (p = 0.05). MMR-D patients with stage I or II and T-bet expression had a significant better survival (p = 0.009). Silencing of MSH2, MLH1 and MSH6, but not PSM2, significantly increased the rate of CD80+ HT29 cells (p = 0.007, p = 0.023 and p = 0.015, respectively).Conclusions CRC with MMR-D showed a higher CD80 expression, and CD8+ and Th1 T-cell infiltration. In vitro silencing of MSH2, MLH1 and MSH6 significantly increased CD80+ cell rate. These results suggest an enhanced immune surveillance mechanism in presence of MMR-D.
    Preview · Article · Oct 2015 · Oncotarget
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