Abstract
Ibrutinib is a known irreversible inhibitor of Bruton tyrosine kinase (BTK) and interleukin‐2‐inducible kinase (ITK). Ibrutinib has multiple immunomodulatory effects and is currently approved for treatment of chronic lymphocytic leukemia (CLL) and other cancers. Although previous studies have shown that ibrutinib inhibits growth of breast cancer cells, its impact on treatment of breast cancer and its metastasis is not determined. Myeloid‐derived Suppressor Cells (MDSCs) are immature myeloid cells present in tumors that can subdue the development of important tumoricidal cell populations, and their presence has been linked to poor prognosis in human and murine models. Here, using an orthotopic mouse breast cancer model, we show that ibrutinib effectively inhibits progression and metastasis of breast cancer. Mice treated with Ibrutinib display significantly lower tumor burdens and metastasis compared to controls. Furthermore, spleens and tumors from Ibrutinib‐treated mice showed higher numbers of mature DCs and lower numbers of myeloid‐derived suppressor Cells (MDSCs) which promote disease progression and are linked to poor prognosis in human and murine models. 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 induction of anti‐tumor TH1 and CTL immune responses. Taken together, our results indicate that Ibrutinib inhibits tumor development and metastasis in breast cancer by promoting development of mature DCs from MDSCs and hence could be a novel therapeutic agent for treatment of breast cancerSupport or Funding InformationPharmacyclics LLC, an AbbVie Company
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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