Premium
Ibrutinib treatment inhibits breast cancer progression and metastasis by inducing conversion of myeloid‐derived suppressor cells to dendritic cells
Author(s) -
Varikuti Sanjay,
Singh Bhawana,
Volpedo Greta,
Ahirwar Dinesh,
Jha Bijay,
Saljoughian Noushin,
Viana Agostinho,
Hamza Omar,
Halsey Gregory,
Holcomb Erin,
Maryala Ritvik,
Oghumu Steve,
Ganju Ramesh K.,
Satoskar Abhay R.
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.06611
Subject(s) - ibrutinib , cancer research , bruton's tyrosine kinase , medicine , metastasis , breast cancer , myeloid , myeloid leukemia , cancer , tyrosine kinase , immunology , leukemia , chronic lymphocytic leukemia , receptor
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 T H 1 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 cancer Support or Funding Information Pharmacyclics LLC, an AbbVie Company