Increased immunogenicity of surviving tumor cells enables cooperation between liposomal doxorubicin and IL-18
Liposomal doxorubicin (Doxil) is a cytotoxic chemotherapy drug with a favorable hematologic toxicity profile. Its active drug, doxorubicin, has interesting immunomodulatory properties.
Here, the effects of Doxil on surviving tumor cell immunophenotype were investigated.
Methods: Using ID8 murine ovarian cancer cells, the immunomodulatory effects of Doxil were studied by measuring its impact on ovarian cancer cell expression of MHC class-I and Fas, and susceptibility to immune attack in vitro. To evaluate the ability of Doxil to cooperate with cancer immunotherapy, the interaction between Doxil and Interleukin 18 (IL-18), a pleiotropic immunostimulatory cytokine, was investigated in vivo in mice bearing ID8-Vegf tumors.
Results: While Doxil killed ID8 tumor cells in a dose-dependent manner, tumor cells escaping Doxil-induced apoptosis upregulated surface expression of MHC-I and Fas, and were sensitized to CTL killing and Fas-mediated death in vitro.
We therefore tested the hypothesis that the combination of immunotherapywith Doxil provides positive interactions. Combination IL-18 and Doxil significantly suppressed tumor growth compared with either monotherapy in vivo and uniquely resulted in complete tumor regression and long term antitumor protection in a significant proportion of mice.
Conclusion: These data demonstrate that Doxil favorably changes the immunophenotype of a large fraction of the tumor that escapes direct killing thus creating an opportunity to expand tumor killing by immunotherapy, which can be capitalized through addition of IL-18 in vivo.
Author: Ioannis AlagkiozidisAndrea FacciabeneCarmine CarpenitoFabian BenenciaZdenka JonakSarah AdamsRichard CarrollPhyllis GimottyRachel HammondGwen-ael Danet-DesnoyersCarl JuneDaniel PowellGeorge Coukos
Credits/Source: Journal of Translational Medicin
Published on: 2009-12-10
Copyright by the authors listed above - made available via BioMedCentral (Open Access). Please
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