Abstract
BackgroundIbrutinib 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.MethodsUsing an orthotopic mouse breast cancer model, we show that ibrutinib inhibits the progression and metastasis of breast cancer.ResultsIbrutinib 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.ConclusionsIbrutinib 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.
Highlights
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
Our results show that T cells co-cultured with myeloid-derived suppressor cells (MDSCs) from ibrutinib-treated mice are able to proliferate significantly more compared to the T cells co-cultured with MDSCs from the vehicle-treated group (Fig. 3c)
In this study, using a murine experimental model of breast cancer, we demonstrate that the potent BTK/inducible tyrosine kinase (ITK) inhibitor ibrutinib is effective in inhibiting breast cancer tumour growth and metastasis
Summary
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. Ibrutinib is highly effective in the treatment of chronic lymphocytic leukaemia (CLL), mantle cell lymphoma, and Waldenstrom’s macroglobulinaemia.[3] Beyond its role in B cell biology, BTK functions have been explored in the maturation, trafficking, and function of myeloid cells,[4,5,6] T cells,[1] and natural killer cells.[7] It is shown that inhibition of ITK by ibrutinib impedes the development of T helper type 2 (TH2) cells and promotes TH1 responses.[1] Rapid binding and high selectivity of ibrutinib reduce the risk of sustained systemic exposures, making it the drug of choice with a well-tolerated dosing regimen as compared to current therapeutic options for the above diseases. Tumour-derived factors can induce DC precursors to migrate to the tumour microenvironment,[9] their presence does not necessarily induce antitumour responses
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