Dual Therapeutic Efficacy of Vinblastine as a Unique Chemotherapeutic Agent Capable of Inducing Dendritic Cell Maturation

Abstract

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 cDNAtransduced 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. [Cancer Res 2009;69(17):6987-94]

Immune-based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer

“…26 Notably, vinblastine at low concentrations (0.1-1 mM) induces phenotypic and functional maturation of DCs in vitro and in vivo, when injected into the skin of mice, by triggering in situ maturation of skin-resident DCs and by boosting humoral and cellular immune responses. 27 A recent study on human 6-sulfo LacNAc þ (slan) DCs, a major subpopulation of human blood DCs, showed that doxorubicin impairs the ability of these cells to produce proinflammatory cytokines and to activate T lymphocytes and NK cells, whereas methotrexate and paclitaxel sustain their effector properties. 28 Cytotoxic chemotherapy can affect DC activities also through indirect mechanisms.…”

Microtubule-Depolymerizing Agents Used in Antibody–Drug Conjugates Induce Antitumor Immunity by Stimulation of Dendritic Cells

“…Although the cancer cell growth-inhibitory properties of dolastatins are several-fold greater than those of vinblastine, we included the latter agent into our experimental set-up based on previously published data showing its capacity to mature DCs (15,16). Following 24-hour culture of SP37A3 cells in the presence of dolastatin 10, dolastatin 15, vinblastine, or LPS, we determined the surface expression of the DC maturation markers CD80, CD86, CD40, and MHC-II ( Fig.…”

“…Nevertheless, only a few studies have been reported that have investigated the capacity of antitumor therapeutics to improve DC function. Recent work has identified several cytotoxic agents, including the mitotic spindle inhibitor vinblastine, as potent activators of DC maturation (14)(15)(16). Although the underlying mechanism is still poorly defined, these data clearly highlight a previously unrecognized immunostimulatory activity for vinblastine.…”

Molecular mechanisms of ATP secretion during immunogenic cell death

“…7,8 Second, multiple chemotherapeutics can directly stimulate antitumor immunity, 1,4 either by potentiating the activity of immune effectors (e.g., vinca alkaloids have been shown to promote the maturation of dendritic cells (DCs)) or by antagonizing immunosuppressive cells (e.g., cyclophosphamide reportedly depletes/inhibits regulatory T cells). 9,10 ICD has been operatively defined as a cell death modality that elicits a protective immune response against dead-cell antigens, implying that the immunogenicity of cell death can be monitored in appropriate vaccination assays. 2,11,12 Thus, the subcutaneous injection of cancer cells that are succumbing to ICD, but not of cells undergoing conventional apoptosis or necrosis, elicits a T-cell-mediated immune response protecting histocompatible mice against a subsequent challenge with tumor cells of the same type.…”