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* Department of Pathology and
Department of Immunology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213; and
Department of Microbiology and Immunology, Institute of Biosciences, São Paulo State University, Caixa Botucatu, São Paulo, Brazil
Antineoplastic chemotherapeutic agents may indirectly activate dendritic cells (DCs) by inducing the release of "danger" signals from dying tumor cells. Whereas the direct cytotoxic or inhibitory effect of conventional chemotherapy on DCs has been reported, modulation of DC function by chemotherapeutic agents in low noncytotoxic concentrations has not yet been investigated. We have tested the effects of different classes of antineoplastic chemotherapeutic agents used in low noncytotoxic concentrations on the Ag-presenting function of DCs. We revealed that paclitaxel, doxorubicin, mitomycin C, and methotrexate up-regulated the ability of DCs to present Ags to Ag-specific T cells. Stimulation of DC function was associated with the up-regulation of expression of Ag-processing machinery components and costimulatory molecules on DCs, as well as increased IL-12p70 expression. However, the ability of DCs treated with paclitaxel, methotrexate, doxorubicin, and vinblastine to increase Ag presentation to Ag-specific T cells was abolished in DCs generated from IL-12 knockout mice, indicating that up-regulation of Ag presentation by DCs is IL-12-dependent and mediated by the autocrine or paracrine mechanisms. At the same time, IL-12 knockout and wild-type DCs demonstrated similar capacity to up-regulate OVA presentation after their pretreatment with low concentrations of mitomycin C and vincristine, suggesting that these agents do not utilize IL-12-mediated pathways in DCs for stimulating Ag presentation. These findings reveal a new mechanism of immunopotentiating activity of chemotherapeutic agents—a direct immunostimulatory effect on DCs (chemomodulation)—and thus provide a strong rationale for further assessment of low-dose chemotherapy given with DC vaccines for cancer treatment.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 These studies were supported by National Institutes of Health Grant RO1 CA084270 (to M.R.S.).
2 Address correspondence and reprint requests to Dr. Galina V. Shurin, Department of Pathology, Division of Experimental Pathology, University of Pittsburgh Medical Center, Scaife Hall S735, 3550 Terrace Street, Pittsburgh, PA. E-mail address: shuringv{at}upmc.edu
3 Abbreviations used in this paper: DC, dendritic cell; APM, Ag-processing machinery; LMP, low molecular mass polypeptide; MFI, mean fluorescence intensity.
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