Silencing of Irf7 pathway in breast cancer cells promotes bone metastasis through immune escape

 Bidwell, BN. et al. Nat Med. 18, 1224-1231 (2012)

Speaker: Shun-Yi Chien (錢舜益)                   )                                 Time: 15:10~16:00, Sep. 26, 2012

Commentator: Dr. Hsiao-Sheng Liu (劉校生博士)     )  Place: Room 601

Abstract

Worldwidely, the survival rate of breast cancer patients decreases because of cancer metastatic spread to other tissues. Many factors influence metastasis, such as intrinsic tumor cell factors, the microenvironment, angiogenesis, and immune response [1]. The authors used syngeneic 4T1.2 mouse model of spontaneous metastasis from the mammary gland to bone to compare the transcriptomes of primary and metastasis tumor cells. To clarify the genes suppressed in metastasis, analysis of the INTERFEROME databases tools [2] was carried out and the results revealed high representation of IFN-regulated genes (IRGs), including the transcription factor IRF7 and 208 of its predicted target genes, as well as upstream regulators,  such as STAT1. Restoration of Irf7 in tumor cells did not affect the proliferation rates of primary tumors, but reduced bone metastasis. The mice bearing 4T1.2 tumors showed higher number of myeloid-derived suppressor cells (MDSCs) than naïve mice in the peripheral blood and bone, and these MDSCs significantly inhibited the proliferation of CD4+ and CD8+ lymphocytes in vitro. Moreover, the authors confirmed the expression of IRF7 in human primary and its loss in distant metastasis, including bone. The high IRF7 expression was significantly associated with the prolonged bone metastasis-free survival. Treatment with IFN-a increased IRF7 expression and reduced the number of MDSCs in peripheral blood and bone. IFN-a had no effects on the growth of primary tumors but caused the extension of metastasis-free survival time. Together, these results reveal IFN specifically inhibits bone metastasis in breast cancer by selective modulation of MDSCs and lymphocytes.

References

1.      Fehm, T., et al. Tumor cell dormancy: implications for the biology and treatment of breast cancer. APMIS 116, 742-753 (2008).

2.      Samarajiwa, S.A., et al. INTERFEROME: the database of interferon regulated genes.  Nucleic Acids Res. 37, D852–D857 (2009).