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    J Interferon Cytokine Res. 2011 Sep;31(9):671-7. doi: 10.1089/jir.2011.0023. Epub 2011 Aug 24.

    The role of Tyk2 in regulation of breast cancer growth.

    Zhang Q, Sturgill JL, Kmieciak M, Szczepanek K, Derecka M, Koebel C, Graham LJ, Dai Y, Chen S, Grant S, Cichy J, Shimoda K, Gamero A, Manjili M, Bear H, Conrad D, Larner AC.

    Source

    Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia 23298, USA.

    Abstract

    The antigrowth and immunomodulatory actions of interferons (IFNs) have enabled these cytokines to be used therapeutically for the treatment of a variety of hematologic and solid malignancies. IFNs exert their effects by activation of the Jak/Stat signaling pathway. IFNγ stimulates the tyrosine kinases Jak1 and Jak2, resulting in activation of the Stat1 transcription factor, whereas type 1 IFNs (IFNα/β) activate Jak1 and Tyk2, which mediate their effects through Stat1 and Stat2. Disruption in the expression of IFNγ, IFNα receptors, or Stat1 inhibits antitumor responses and blunt cancer immunosurveillance in mice. Mutations in Jak2 or constitutive activation of Jak1 or Jak2 also promote the development of a variety of malignancies. Although there are data indicating that Tyk2 plays a role in the pathogenesis of lymphomas, the effects of Tyk2 expression on tumorigenesis are unknown. We report here that Tyk2(-/-) mice inoculated with 4T1 breast cancer cells show enhanced tumor growth and metastasis compared to Tyk2(+/+) animals. Accelerated growth of 4T1 cells in Tyk2(-/-) animals does not appear to be due to decreased function of CD4(+), CD8(+) T cells, or NK cells. Rather, the tumor suppresive effects of Tyk2 are mediated at least in part by myeloid-derived suppressor cells, which appear to be more effective in inhibiting T cell responses in Tyk2(-/-) mice. Our results provide the first evidence for a role of Tyk2 in suppressing the growth and metastasis of breast cancer.

    PMID:
    21864028
    [PubMed - indexed for MEDLINE]
    PMCID:
    PMC3173819
    Free PMC Article

    Images from this publication. See all images (7)   Free text

    FIG. 3.
    FIG. 3.
    Tyk2 deficiency promotes metastasis in the absence of a primary tumor. Mice were inoculated with 4T1 cells by tail vein injection. After 10 days, lungs and livers were collected. Metastasis was measured by clonogenic assay. (A) Metastatic colonies in the livers. (B) Metastatic colonies in the lungs. Eight Tyk2+/+ and Tyk2−/− mice were used for these experiments.
    J Interferon Cytokine Res. 2011 September;31(9):671-677.
    FIG. 5.
    FIG. 5.
    Expression of Tyk2 in NK cells does not contribute to 4T1 cell tumor genesis. (A) Protocol for in vivo NK cell depletion. One day before 4T1 cell inoculation Tyk2+/+ or Tyk2−/− mice were injected with 200 μg of anti-asialo GM1 or control serum. Antibody injections were continued on days 7, 14, and 21, where day 2 is the day of tumor challenge. (B) Efficiency of NK cell depletion by flow cytometry is displayed in the FACS scans. (C) NK cells do not contribute to enhanced growth of 4T1 cells in Tyk2−/− mice. Tumor volume (mm3) was measured 23 days after inoculation (top panel). Data bars represent the mean±standard errors. Although there was a slight increase in tumor volumes in both Tyk2+/+ and Tyk2−/− mice depleted of NK cells, tumors in Tyk2−/− mice remained increased compared to Tyk2+/+ mice in the absence of NK cells.
    J Interferon Cytokine Res. 2011 September;31(9):671-677.
    FIG. 7.
    FIG. 7.
    Tumor-bearing Tyk2−/− mice have higher levels of myeloid derived suppressor cells (MDSCs) than tumor-bearing Tyk2+/+ animals. (A) Mice were inoculated with 4T1 cells, and 22 days later spleens were harvested and stained for MDSCs. Each group had 3 mice. Data bars represent the mean±standard deviation. Tyk2+/+ and Tyk2−/− mice were inoculated with 4T1 cells. Seventeen days later MDSCs from spleens were collected by sorting for CD11b+Gr1+cells. MDSCs (0.5×106) were incubated with naïve splenocytes (106) labeled with carboxyfluorescein diacetate, succinimidyl ester. After 48 h incubation, cells were stained with anti-CD3-PE and anti-CD4-PE/Cy5 or anti-CD8a-PE.Cy5. (B) MDSCs are more effective than Tyk2+/+ MDSCs in suppressing T cell proliferation. CD4+ T cell proliferation was measured in cells isolated from Tyk2+/+ or Tyk2−/− mice (C) CD8+ T cell proliferation was measured under the same conditions as CD4+ cells.
    J Interferon Cytokine Res. 2011 September;31(9):671-677.
    FIG. 1.
    FIG. 1.
    4T1 cells show enhanced tumor growth in Tyk2−/− mice. Tyk2+/+ and Tyk2−/− female mice (n=12 for each genotype) were inoculated with 4T1 cells in the abdominal mammary gland and tumor growth was monitored. Twenty-nine days after inoculation, mice were sacrificed and primary tumors were collected and weighed (A) Tumor volumes were measured using Vernier calipers. (B) Primary tumor weights. (C) Spleen weights. Each group contained 12 mice. Data bars represent the mean±standard errors. These data are pooled from 2 experiments. Data bars represent the mean±standard errors (P<0.0001). These data are pooled from 2 experiments.
    J Interferon Cytokine Res. 2011 September;31(9):671-677.
    FIG. 2.
    FIG. 2.
    Tyk2−/− mice inoculated with 4T1 cells display increased metastatic disease. Tyk2+/+ and Tyk2−/− mice (n=12) were injected with 4T1 cells in the abdominal mammary gland. Twenty-nine days after inoculation, mice were sacrificed and livers and lungs were collected. Cells isolated from these tissues were plated on 6-thioguanine and colonies were counted after 12–14 days. (A) Numbers of liver metastases. (B) Numbers of lung metastasis. Each group contained 12 mice. These data are pooled from 2 experiments.
    J Interferon Cytokine Res. 2011 September;31(9):671-677.
    FIG. 4.
    FIG. 4.
    Tyk2−/− splenocytes sensitized to 4T1 cells produce less interferon-γ (IFNγ) than Tyk2+/+ splenocytes. Mice (n=8) were inoculated with 4T1 cells. After 5 days, spleens were harvested. (A) Splenocytes (5×106) were cocultured with IL-2 in the presence or absence of irradiated 4T1 (4×105 cells) (15,000 rads). After 24 h, the supernatants were collected and IFNγ concentration was determined using an IFNγ ELISA kit. Data bars represent means and standard errors p<0.03. (B) IFNγ production in tumors isolated from mice inoculated with 4T1 cells was measured as described. Tumors were harvested 7 days after introduction of 4T1 cells into Tyk2+/+ or Tyk2−/− mice (p<0.05).
    J Interferon Cytokine Res. 2011 September;31(9):671-677.
    FIG. 6.
    FIG. 6.
    Expression of Tyk2 in CD4+ or CD8+ cells does not contribute to 4T1 cell tumor genesis. (A) CD4+ T cell depletion does not change 4T1 tumor growth. Tumor volume (mm3) was measured 19 days after inoculation with 4T1 cells. Data bars represent the mean±standard errors. CD4+ T cell-depleted group had 8 mice; other groups had 6 mice. P<0.001. (B) CD8+ T cell depletion does not contribute to increased primary tumor growth in Tyk2−/− mice. Tumor volume (mm3) was measured 19 days after inoculation. Although there was a slight increase in tumor volumes in both Tyk2+/+ and Tyk2−/− mice depleted of CD8+ cells, tumors in Tyk2−/− mice remained increased compared to Tyk2+/+ mice in the absence of CD8+ cells. Data bars represent the mean±standard errors. CD8+ T cell-depleted group had 8 mice; other groups had 6 mice. P<0.0001.
    J Interferon Cytokine Res. 2011 September;31(9):671-677.

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