title: Antitumor T-cell responses contribute to the effects of dasatinib on c-KIT mutant murine mastocytoma and are potentiated by anti-OX40.
abstract: Targeted and immune-based therapies are thought to eradicate cancer cells by different mechanisms, and these approaches could possibly complement each other when used in combination. In this study, we report that the in vivo antitumor effects of the c-KIT inhibitor, dasatinib, on the c-KIT mutant P815 mastocytoma tumor were substantially dependent on T cell-mediated immunity. We found that dasatinib treatment significantly decreased levels of Tregs while specifically enhancing tumor antigen-specific T-cell responses. We sought to further enhance this therapy with the addition of anti-OX40 antibody, which is known to provide a potent costimulatory signal to T cells. The combination of dasatinib and anti-OX40 antibody resulted in substantially better therapeutic efficacy compared with either drug alone, and this was associated with enhanced accumulation of tumor antigen-specific T cells in the tumor microenvironment. Furthermore, the combination regimen inhibited the function of Tregs and also resulted in significantly up-regulated expression of the IFN-γ-induced chemokines CXCL9, 10, and 11 in the tumor microenvironment, which provides a feasible mechanism for the enhanced intratumoral CTL infiltration. These studies delineate a strategy by which targeted therapy and immunotherapy may be combined to achieve superior antitumor responses in cancer patients.
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yang
authors.forename: Chengwen
authors.initials: C
authors.lastname: Liu
authors.forename: Weiyi
authors.initials: W
authors.lastname: Peng
authors.forename: Gregory
authors.initials: G
authors.lastname: Lizée
authors.forename: Willem W
authors.initials: WW
authors.lastname: Overwijk
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.forename: Scott E
authors.initials: SE
authors.lastname: Woodman
authors.forename: Patrick
authors.initials: P
authors.lastname: Hwu
mesh_terms: D000818:Animals; D000906:Antibodies / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D045744:Cell Line, Tumor; D018925:Chemokines / Q000235:genetics / Q000276:immunology; D000069439:Dasatinib; D004334:Drug Administration Schedule; D004357:Drug Synergism; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D034801:Mastocytoma / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D051379:Mice; D008811:Mice, Inbred DBA; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000276:immunology; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D053262:Receptors, OX40 / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D059016:Tumor Microenvironment / Q000187:drug effects / Q000235:genetics / Q000276:immunology
chemical_list: D000906:Antibodies; D018925:Chemokines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D053262:Receptors, OX40; D013844:Thiazoles; D007371:Interferon-gamma; D019009:Proto-Oncogene Proteins c-kit; D000069439:Dasatinib