title: Myeloid-Derived Suppressor Cells Express Bruton's Tyrosine Kinase and Can Be Depleted in Tumor-Bearing Hosts by Ibrutinib Treatment.
abstract: Myeloid-derived suppressor cells (MDSC) are a heterogeneous group of immature myeloid cells that expand in tumor-bearing hosts in response to soluble factors produced by tumor and stromal cells. MDSC expansion has been linked to loss of immune effector cell function and reduced efficacy of immune-based cancer therapies, highlighting the MDSC population as an attractive therapeutic target. Ibrutinib, an irreversible inhibitor of Bruton's tyrosine kinase (BTK) and IL2-inducible T-cell kinase (ITK), is in clinical use for the treatment of B-cell malignancies. Here, we report that BTK is expressed by murine and human MDSCs, and that ibrutinib is able to inhibit BTK phosphorylation in these cells. Treatment of MDSCs with ibrutinib significantly impaired nitric oxide production and cell migration. In addition, ibrutinib inhibited in vitro generation of human MDSCs and reduced mRNA expression of indolamine 2,3-dioxygenase, an immunosuppressive factor. Treatment of mice bearing EMT6 mammary tumors with ibrutinib resulted in reduced frequency of MDSCs in both the spleen and tumor. Ibrutinib treatment also resulted in a significant reduction of MDSCs in wild-type mice bearing B16F10 melanoma tumors, but not in X-linked immunodeficiency mice (XID) harboring a BTK mutation, suggesting that BTK inhibition plays an important role in the observed reduction of MDSCs in vivo Finally, ibrutinib significantly enhanced the efficacy of anti-PD-L1 (CD274) therapy in a murine breast cancer model. Together, these results demonstrate that ibrutinib modulates MDSC function and generation, revealing a potential strategy for enhancing immune-based therapies in solid malignancies. Cancer Res; 76(8); 2125-36. ©2016 AACR.
authors.affiliation: Medical Scientist Training Program, Columbus, Ohio. Biomedical Sciences Graduate Program, The Ohio State University, Columbus, Ohio.
authors.forename: Andrew
authors.initials: A
authors.lastname: Stiff
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Prashant
authors.initials: P
authors.lastname: Trikha
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio.
authors.forename: Robert
authors.initials: R
authors.lastname: Wesolowski
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio.
authors.forename: Kari
authors.initials: K
authors.lastname: Kendra
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Vincent
authors.initials: V
authors.lastname: Hsu
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Sarvani
authors.initials: S
authors.lastname: Uppati
authors.affiliation: Biomedical Sciences Graduate Program, The Ohio State University, Columbus, Ohio.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: McMichael
authors.affiliation: Biomedical Sciences Graduate Program, The Ohio State University, Columbus, Ohio.
authors.forename: Megan
authors.initials: M
authors.lastname: Duggan
authors.affiliation: Medical Scientist Training Program, Columbus, Ohio. Biomedical Sciences Graduate Program, The Ohio State University, Columbus, Ohio.
authors.forename: Amanda
authors.initials: A
authors.lastname: Campbell
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Karen
authors.initials: K
authors.lastname: Keller
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Ian
authors.initials: I
authors.lastname: Landi
authors.affiliation: Division of Hematology, Department of Internal Medicine and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Yiming
authors.initials: Y
authors.lastname: Zhong
authors.affiliation: Division of Hematology, Department of Internal Medicine and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Jason
authors.initials: J
authors.lastname: Dubovsky
authors.affiliation: Department of Internal Medicine and Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio.
authors.forename: John Harrison
authors.initials: JH
authors.lastname: Howard
authors.affiliation: Department of Biomedical Informatics, The Ohio State University, Columbus, Ohio.
authors.forename: Lianbo
authors.initials: L
authors.lastname: Yu
authors.affiliation: Division of Hematology, Department of Internal Medicine and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Bonnie
authors.initials: B
authors.lastname: Harrington
authors.affiliation: Department of Otolaryngology, The Ohio State University, Columbus, Ohio.
authors.forename: Matthew
authors.initials: M
authors.lastname: Old
authors.affiliation: Medical Scientist Training Program, Columbus, Ohio. Biomedical Sciences Graduate Program, The Ohio State University, Columbus, Ohio.
authors.forename: Sean
authors.initials: S
authors.lastname: Reiff
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio.
authors.forename: Thomas
authors.initials: T
authors.lastname: Mace
authors.affiliation: Biomedical Sciences Graduate Program, The Ohio State University, Columbus, Ohio. Department of Internal Medicine and Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio.
authors.forename: Susheela
authors.initials: S
authors.lastname: Tridandapani
authors.affiliation: Division of Hematology, Department of Internal Medicine and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Natarajan
authors.initials: N
authors.lastname: Muthusamy
authors.affiliation: Division of Hematology, Department of Internal Medicine and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Caligiuri
authors.affiliation: Division of Hematology, Department of Internal Medicine and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
authors.affiliation: Division of Surgical Oncology, Department of Surgery and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio. william.carson@osumc.edu.
authors.forename: William E
authors.initials: WE
authors.lastname: Carson
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D016207:Cytokines / Q000096:biosynthesis; D015870:Gene Expression; D006801:Humans; D007167:Immunotherapy; D051379:Mice; D000072737:Myeloid-Derived Suppressor Cells / Q000201:enzymology*; D010880:Piperidines; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011720:Pyrazoles / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
chemical_list: D016207:Cytokines; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse; D000225:Adenine