Using a breast cancer mouse model, Varikuti and Singh et al. studied the effects of ibrutinib (a BTK/ITK inhibitor) on myeloid-derived suppressor cells (MDSCs), which are linked to poor prognosis. Ibrutinib treatment decreased tumor growth and metastasis to the lungs, and converted spleen- and tumor-derived monocytic MDSCs to mature dendritic cells with enhanced MHC-II expression. Splenocytes from tumor-bearing mice treated with ibrutinib showed increased CD8+ T cell proliferation and TH1 cytokine production, suggesting antitumor activity of ibrutinib is partly mediated by reprogramming MDSCs and promoting TH1-mediated tumor immunity.
Contributed by Katherine Turner
BACKGROUND: Ibrutinib is a Bruton's tyrosine kinase (BTK) and interleukin-2-inducible kinase (ITK) inhibitor used for treating chronic lymphocytic leukaemia (CLL) and other cancers. Although ibrutinib is known to inhibit the growth of breast cancer cell growth in vitro, its impact on the treatment and metastasis of breast cancer is unclear. METHODS: Using an orthotopic mouse breast cancer model, we show that ibrutinib inhibits the progression and metastasis of breast cancer. RESULTS: Ibrutinib inhibited proliferation of cancer cells in vitro, and Ibrutinib-treated mice displayed significantly lower tumour burdens and metastasis compared to controls. Furthermore, the spleens and tumours from Ibrutinib-treated mice contained more mature DCs and lower numbers of myeloid-derived suppressor cells (MDSCs), which promote disease progression and are linked to poor prognosis. We also confirmed that ex vivo treatment of MDSCs with ibrutinib switched their phenotype to mature DCs and significantly enhanced MHCII expression. Further, ibrutinib treatment promoted T cell proliferation and effector functions leading to the induction of antitumour TH1 and CTL immune responses. CONCLUSIONS: Ibrutinib inhibits tumour development and metastasis in breast cancer by promoting the development of mature DCs from MDSCs and hence could be a novel therapeutic agent for the treatment of breast cancer.
Author Info: (1) Department of Pathology, The Ohio State University Medical Center, Columbus, OH, USA. (2) Department of Pathology, The Ohio State University Medical Center, Columbus, OH, USA.
Author Info: (1) Department of Pathology, The Ohio State University Medical Center, Columbus, OH, USA. (2) Department of Pathology, The Ohio State University Medical Center, Columbus, OH, USA. (3) Department of Pathology, The Ohio State University Medical Center, Columbus, OH, USA. Department of Microbiology, The Ohio State University, Columbus, OH, USA. (4) Department of Pathology, The Ohio State University Medical Center, Columbus, OH, USA. (5) Department of Infection and Immunity, The Ohio State University, Columbus, OH, USA. (6) Department of Pathology, The Ohio State University Medical Center, Columbus, OH, USA. (7) Department of Pathology, The Ohio State University Medical Center, Columbus, OH, USA. (8) Department of Pathology, The Ohio State University Medical Center, Columbus, OH, USA. (9) Department of Pathology, The Ohio State University Medical Center, Columbus, OH, USA. (10) Department of Pathology, The Ohio State University Medical Center, Columbus, OH, USA. (11) Department of Pathology, The Ohio State University Medical Center, Columbus, OH, USA. (12) Department of Pathology, The Ohio State University Medical Center, Columbus, OH, USA. (13) Department of Pathology, The Ohio State University Medical Center, Columbus, OH, USA. (14) Department of Pathology, The Ohio State University Medical Center, Columbus, OH, USA. (15) Department of Pathology, The Ohio State University Medical Center, Columbus, OH, USA. abhay.satoskar@osumc.edu. Department of Microbiology, The Ohio State University, Columbus, OH, USA. abhay.satoskar@osumc.edu.
