title: Dasatinib Changes Immune Cell Profiles Concomitant with Reduced Tumor Growth in Several Murine Solid Tumor Models.
abstract: Dasatinib, a broad-range tyrosine kinase inhibitor, induces rapid mobilization of lymphocytes and clonal expansion of cytotoxic cells in leukemia patients. Here, we investigated whether dasatinib could induce beneficial immunomodulatory effects in solid tumor models. The effects on tumor growth and on the immune system were studied in four different syngeneic mouse models (B16.OVA melanoma, 1956 sarcoma, MC38 colon, and 4T1 breast carcinoma). Both peripheral blood (PB) and tumor samples were immunophenotyped during treatment. Although in vitro dasatinib displayed no direct cytotoxicity to B16 melanoma cells, a significant decrease in tumor growth was observed in dasatinib-treated mice compared with vehicle-treated group. Further, dasatinib-treated melanoma-bearing mice had an increased proportion of CD8+T cells in PB, together with a higher amount of tumor-infiltrating CD8+T cells. Dasatinib-mediated antitumor efficacy was abolished when CD4+and CD8+T cells were depleted with antibodies. Results were confirmed in sarcoma, colon, and breast cancer models, and in all cases mice treated daily with dasatinib had a significant decrease in tumor growth. Detailed immunophenotyping of tumor tissues with CyTOF indicated that dasatinib had reduced the number of intratumoral regulatory T cells in all tumor types. To conclude, dasatinib is able to slow down the tumor growth of various solid tumor models, which is associated with the favorable blood/tumor T-cell immunomodulation. The assessment of synergistic combinatorial therapies with other immunomodulatory drugs or targeted small-molecule oncokinase inhibitors is warranted in future clinical trials. Cancer Immunol Res; 5(2); 157-69. ©2017 AACR.
authors.affiliation: Hematology Research Unit Helsinki, Department of Hematology, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland.
authors.forename: Can
authors.initials: C
authors.lastname: Hekim
authors.affiliation: Hematology Research Unit Helsinki, Department of Hematology, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland.
authors.forename: Mette
authors.initials: M
authors.lastname: Ilander
authors.affiliation: Bristol-Myers Squibb Research and Development, Princeton, New Jersey.
authors.forename: Jun
authors.initials: J
authors.lastname: Yan
authors.affiliation: Bristol-Myers Squibb Research and Development, Princeton, New Jersey.
authors.forename: Erin
authors.initials: E
authors.lastname: Michaud
authors.affiliation: Bristol-Myers Squibb Research and Development, Princeton, New Jersey.
authors.forename: Richard
authors.initials: R
authors.lastname: Smykla
authors.affiliation: Cancer Gene Therapy Group, Department of Pathology and Transplantation Laboratory, Haartman Institute, University of Helsinki, Finland.
authors.forename: Markus
authors.initials: M
authors.lastname: Vähä-Koskela
authors.affiliation: Hematology Research Unit Helsinki, Department of Hematology, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland.
authors.forename: Paula
authors.initials: P
authors.lastname: Savola
authors.affiliation: Cancer Gene Therapy Group, Department of Pathology and Transplantation Laboratory, Haartman Institute, University of Helsinki, Finland.
authors.forename: Siri
authors.initials: S
authors.lastname: Tähtinen
authors.affiliation: Department of Pathology, HUSLAB and Haartman Institute, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland.
authors.forename: Leena
authors.initials: L
authors.lastname: Saikko
authors.affiliation: Cancer Gene Therapy Group, Department of Pathology and Transplantation Laboratory, Haartman Institute, University of Helsinki, Finland.
authors.forename: Akseli
authors.initials: A
authors.lastname: Hemminki
authors.affiliation: Department of Pathology, HUSLAB and Haartman Institute, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland.
authors.forename: Panu E
authors.initials: PE
authors.lastname: Kovanen
authors.affiliation: Hematology Research Unit Helsinki, Department of Hematology, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland.
authors.forename: Kimmo
authors.initials: K
authors.lastname: Porkka
authors.affiliation: Bristol-Myers Squibb Research and Development, Princeton, New Jersey.
authors.forename: Francis Y F
authors.initials: FY
authors.lastname: Lee
authors.affiliation: Hematology Research Unit Helsinki, Department of Hematology, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland. satu.mustjoki@helsinki.fi.|Department of Clinical Chemistry, University of Helsinki, Helsinki, Finland.
authors.forename: Satu
authors.initials: S
authors.lastname: Mustjoki
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D000069439:Dasatinib / Q000494:pharmacology*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D056747:Immunomodulation / Q000187:drug effects*; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008546:Melanoma, Experimental; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D000069439:Dasatinib