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The Interferon-Gamma Paradox in Cancer.

ABSTRACT: Interferon-gamma (IFNG) has long been implicated as a central orchestrator of antitumor immune responses in the elimination stage of the immunoediting paradigm. However, mounting evidence suggests that IFNG may also have important and significant protumor roles to play in the equilibrium and escape phases through its regulatory effects on immunoevasive functions that promote tumorigenesis. These seemingly contradictory effects of IFNG undoubtedly play profound roles in not only the activation of inflammatory response to cancer but also in the determination of its outcome. In the face of the recent explosion of anticancer immunotherapeutic strategies in the clinic, it is critical that a complete understanding is achieved of the underpinnings of the mechanisms that determine the two faces of IFNG signaling in cancer. Here, the current state of this dichotomy is reviewed.

SUBMITTER: Zaidi MR

PROVIDER: S-EPMC6350411 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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The Interferon-Gamma Paradox in Cancer.

Zaidi M Raza MR

Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 20181109 1

Interferon-gamma (IFNG) has long been implicated as a central orchestrator of antitumor immune responses in the elimination stage of the immunoediting paradigm. However, mounting evidence suggests that IFNG may also have important and significant protumor roles to play in the equilibrium and escape phases through its regulatory effects on immunoevasive functions that promote tumorigenesis. These seemingly contradictory effects of IFNG undoubtedly play profound roles in not only the activation of ...[more]

PMID: 30388040

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Project description:BackgroundDespite improvements in disease diagnosis, treatment, and prognosis, breast cancer is still a leading cause of cancer death for women. Compelling evidence suggests that targeting cancer stem cells (CSCs) have a crucial impact on overcoming the current shortcomings of chemotherapy and radiotherapy. In the present study, we aimed to study the effects of T cells and a critical anti-tumor cytokine, interferon-gamma (IFN-γ), on breast cancer stem cells.MethodsBALB/c mice and BALB/c nude mice were subcutaneously injected with 4T1 tumor cells. Tumor growth and pulmonary metastasis were assessed. ALDEFLOUR™ assays were performed to identify aldehyde dehydrogenasebright (ALDHbr) tumor cells. ALDHbr cells as well as T cells from tumor-bearing BALB/c mice were analyzed using flow cytometry. The effects of CD8+ T cells on ALDHbr tumor cells were assessed in vitro and in vivo. The expression profiles of ALDHbr and ALDHdim 4T1 tumor cells were determined. The levels of plasma IFN-γ were measured by enzyme-linked immunosorbent assay, and their associations with the percentages of ALDHbr tumor cells were evaluated. The effects of IFN-γ on ALDH expression and the malignancy of 4T1 tumor cells were analyzed in vitro.ResultsThere were fewer metastatic nodules in tumor-bearing BALB/c mice than those in tumor-bearing BALB/c nude mice (25.40 vs. 54.67, P < 0.050). CD8+ T cells decreased the percentages of ALDHbr 4T1 tumor cells in vitro (control vs. effector to target ratio of 1:1, 10.15% vs. 5.76%, P < 0.050) and in vivo (control vs. CD8+ T cell depletion, 10.15% vs. 21.75%, P < 0.001). The functions of upregulated genes in ALDHbr 4T1 tumor cells were enriched in the pathway of response to IFN-γ. The levels of plasma IFN-γ decreased gradually in tumor-bearing BALB/c mice, while the percentages of ALDHbr tumor cells in primary tumors increased. IFN-γ at a concentration of 26.68 ng/mL decreased the percentages of ALDHbr 4T1 tumor cells (22.88% vs. 9.88%, P < 0.050) and the protein levels of aldehyde dehydrogenase 1 family member A1 in 4T1 tumor cells (0.86 vs. 0.49, P < 0.050) and inhibited the abilities of sphere formation (sphere diameter <200 μm, 159.50 vs. 72.0; ≥200 μm, 127.0 vs. 59.0; both P < 0.050) and invasion (89.67 vs. 67.67, P < 0.001) of 4T1 tumor cells.ConclusionCD8+ T cells and IFN-γ decreased CSC numbers in a 4T1 mouse model of breast cancer. The application of IFN-γ may be a potential strategy for reducing CSCs in breast cancer.

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The Interferon-Gamma Paradox in Cancer.

Publications

The Interferon-Gamma Paradox in Cancer.

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