Journal Article

Ibrutinib treatment inhibits breast cancer progression and metastasis by inducing conversion of myeloid-derived suppressor cells to dendritic cells

Ganju, Ramesh K., Holcomb, Erin A., Ahirwar, Dinesh K., Verma, Chaitenya, Maryala, Ritvik J., Viana, Agostinho G., Hamza, Omar, Halsey, Gregory, Saljoughian, Noushin, Oghumu, Steve, Jha, Bijay K., Singh, Bhawana, Volpedo, Greta, Satoskar, Abhay R., Varikuti, Sanjay

2020

Overview

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 T H 1 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/67 / 692/4028 / Adenine - analogs & derivatives / Adenine - pharmacology / Adenine - therapeutic use / Animals / Biomedical and Life Sciences / Biomedicine / Breast cancer / Breast Neoplasms - drug therapy / Breast Neoplasms - pathology / Bruton's tyrosine kinase / Cancer Research / Cell growth / Cell proliferation / Chronic lymphocytic leukemia / Cytotoxicity / Dendritic cells / Dendritic Cells - metabolism / Disease Progression / Drug Resistance / Enzyme inhibitors / Epidemiology / Female / Humans / Inhibitor drugs / Interleukin 2 / Itk protein / Kinases / Leukemia / Lymphocytes T / Metastases / Metastasis / Mice / Molecular Medicine / Myeloid-Derived Suppressor Cells - metabolism / Neoplasm Metastasis - drug therapy / Oncology / Phenotypes / Piperidines - pharmacology / Piperidines - therapeutic use / Protein-tyrosine kinase / Suppressor cells / Targeted cancer therapy / Tumors