Bottos, Alessia, Gotthardt, Dagmar, Gill, Jason W, Gattelli, Albana, Frei, Anna, Tzankov, Alexandar, Sexl, Veronika, Wodnar-Filipowicz, Aleksandra and Hynes, Nancy E (2016) Decreased NK cell-mediated anti-tumor immunity consequent to JAK pathway inhibition enhances metastasis in preclinical models of breast cancer. Nat Commun., 7 (12258). pp. 1-12. ISSN 2041-1723

Abstract

The JAK/STAT pathway is an attractive target for breast cancer therapy due to its frequent activation1,2. Clinical trials evaluating the efficacy of JAK inhibitors (JAKi) in advanced breast cancer are ongoing3, making it important to understand the effect of this therapeutic approach on metastasis. Using patient biopsies and preclinical models of breast cancer, we demonstrate that the JAK/STAT pathway is active in metastasis. Unexpectedly, blocking the pathway with the JAKi ruxolitinib and BSK805 enhanced the metastatic burden in experimental and orthotopic models of breast cancer metastasis. We demonstrate that this pro-metastatic effect is due to the immunosuppressive activity of JAKi with ensuing impairment of NK cell-mediated anti-tumor immunity. Furthermore, we show that immunostimulation with IL15 overcomes the enhancing effect of JAKi on experimental metastasis formation. Our findings highlight the importance of evaluating the effect of targeted therapy on the tumor environment, in addition to the cancer cells. The impact of JAKi on NK cells, and the potential value of immunostimulators to overcome the weakened tumor immunosurveillance, is worthwhile considering in the clinical setting of breast cancer.

Item Type:	Article
Date Deposited:	12 Aug 2016 00:45
Last Modified:	12 Aug 2016 00:45
URI:	https://oak.novartis.com/id/eprint/28562