Dual therapeutic efficacy of vinblastine as a unique chemotherapeutic agent capable of inducing dendritic cell maturation
Our recent unbiased functional screen of 54 chemotherapeutic drugs unveiled striking heterogeneity in their effects on dendritic cells (DC). Most notably, vinblastine (VBL) was found to induce phenotypic and functional maturation of DCs in vitro. Here, we sought to determine whether VBL exhibits "dual" therapeutic efficacy in living animals by directly killing tumor cells and by boosting host immunity via DC maturation. Local injection of VBL in a low dose into the skin of C57BL/6 mice induced in situ maturation of epidermal Langerhans cells. When coinjected with a model antigen, ovalbumin (OVA), VBL enhanced OVA-specific cellular and humoral immune responses. When injected directly into the OVA cDNA-transduced E.G7 tumors, VBL augmented clonal expansion of OVA-reactive CD8 T cells and CTL activities. In B16 melanoma model, intratumor VBL injection induced apoptosis of melanoma cells, phenotypic maturation of tumor-infiltrating DCs, and significant CTL activities. Although complete clearance was never achieved, growth kinetic of B16 melanoma was markedly reduced in C57BL/6 mice by intratumor VBL injection. Importantly, the same treatment was far less efficacious in immunocompromised severe combined immunodeficient mice, indicating the requirement of intact host immunity. Our results introduce a new concept that VBL may be used to design "immunostimulatory" chemotherapy regimens.
|Keywords||CD8+ T lymphocyte, Langerhans cell, SCID mouse, animal cell, animal experiment, animal model, antigen, antineoplastic agent, apoptosis, article, cell infiltration, cell maturation, cell migration, cellular immunity, complementary DNA, controlled study, cytotoxic T lymphocyte, dendritic cell, drug activity, drug efficacy, humoral immunity, immunity, low drug dose, lymph node, melanoma, mouse, nonhuman, ovalbumin, phenotype, priority journal, tumor cell, vinblastine|
|Persistent URL||dx.doi.org/10.1158/0008-5472.CAN-09-1106, hdl.handle.net/1765/17547|
Tanaka, H, Matsushima, H, Nishibu, A, Clausen, B.E, & Takashima, A. (2009). Dual therapeutic efficacy of vinblastine as a unique chemotherapeutic agent capable of inducing dendritic cell maturation. Cancer Research, 69(17), 6987–6994. doi:10.1158/0008-5472.CAN-09-1106