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Low-Dose Paclitaxel Prior to Intratumoral Dendritic Cell Vaccine Modulates Intratumoral Cytokine Network and Lung Cancer Growth

Authors' Affiliations: ¹ Shanghai Chest Hospital, Shanghai, China; Departments of ² Pathology, ³ Medicine, and ⁴ Immunology, University of Pittsburgh Medical Center; and ⁵ Molecular Biosensors and Imaging Center, Carnegie Mellon University, Pittsburgh, Pennsylvania

Requests for reprints: Galina V. Shurin, Department of Pathology, University of Pittsburgh Medical Center, Scaife Hall, Room S733, 3550 Terrace Street, Pittsburgh, PA 15261. Phone: 412-648-9831; Fax: 412-648-8158; E-mail: shuringv{at}upmc.edu.

Purpose: The main goal of this study was to provide the "proof-of-principle" that low-dose paclitaxel is able to change the tumor microenvironment and improve the outcome of intratumoral dendritic cell vaccine in a murine lung cancer model.

Experimental Design: We evaluated the antitumor potential and changes in the intratumoral milieu of a combination of low-dose chemotherapy and dendritic cell vaccine in the Lewis lung carcinoma model in vivo.

Results: The low-dose paclitaxel, which induced apoptosis in 10% of tumor cells, was not toxic to bone marrow cells and dendritic cells and stimulated dendritic cell maturation and function in vitro. Although tumor cells inhibited dendritic cell differentiation in vitro, this immunosuppressive effect was abrogated by the pretreatment of tumor cells with low-dose paclitaxel. Based on these data, we next tested whether pretreatment of tumor-bearing mice with low-dose paclitaxel in vivo would improve the antitumor potential of dendritic cell vaccine administered intratumorally. Significant inhibition of tumor growth in mice treated with low-dose paclitaxel plus intratumoral dendritic cell vaccine, associated with increased tumor infiltration by CD4⁺ and CD8⁺ T cells and elevated tumor-specific IFN- production by draining lymph node cells, was revealed. Using a novel intratumoral microdialysis technique and Luminex technology for collecting and characterizing soluble factors released within the tumor bed for several days in live freely moving animals, we showed that low-dose paclitaxel altered the cytokine network at the tumor site.

Conclusions: Our data indicate that low-dose chemotherapy before intratumoral delivery of dendritic cells might be associated with beneficial alterations of the intratumoral microenvironment and thus support antitumor immunity.