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Small Rho GTPases Mediate Tumor-Induced Inhibition of Endocytic Activity of Dendritic Cells¹

Irina L. Tourkova^*, Galina V. Shurin^*, Sheng Wei and Michael R. Shurin^2,*,

^* Department of Pathology and Department of Immunology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213; and H. Lee Moffitt Cancer Center, University of South Florida, Tampa, FL 33612

The generation, maturation, and function of dendritic cells (DC) have been shown to be markedly compromised in the tumor microenvironment in animals and humans. However, the molecular mechanisms and intracellular pathways involved in the regulation of the DC system in cancer are not yet fully understood. Recently, we have reported on the role of the small Rho GTPase family members Cdc42, Rac1, and RhoA in regulating DC adherence, motility, and Ag presentation. To investigate involvement of small Rho GTPases in dysregulation of DC function by tumors, we next evaluated how Cdc42, Rac1, and RhoA regulated endocytic activity of DC in the tumor microenvironment. We revealed a decreased uptake of dextran 40 and polystyrene beads by DC generated in the presence of different tumor cell lines, including RM1 prostate, MC38 colon, 3LL lung, and B7E3 oral squamous cell carcinomas in vitro and by DC prepared from tumor-bearing mice ex vivo. Impaired endocytic activity of DC cocultured with tumor cells was associated with decreased levels of active Cdc42 and Rac1. Transduction of DC with the dominant negative Cdc42 and Rac1 genes also led to reduced phagocytosis and receptor-mediated endocytosis. Furthermore, transduction of DC with the constitutively active Cdc42 and Rac1 genes restored endocytic activity of DC that was inhibited by the tumors. Thus, our results suggest that tumor-induced dysregulation of endocytic activity of DC is mediated by reduced activity of several members of the small Rho GTPase family, which might serve as new targets for improving the efficacy of DC vaccines.

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 This work was supported by National Institutes of Health Grant 2RO1 CA 084270 (to M.R.S.).

² Address correspondence and reprint requests Dr. Michael R. Shurin, Clinical Immunopathology, 5725 CHP MT, 200 Lothrop Street, Pittsburgh, PA 15213. E-mail address: shurinmr{at}upmc.edu

³ Abbreviations used in this paper: DC, dendritic cell; CM, complete medium; VV, Vaccinia virus; dn, dominant negative; ca, constitutively active; MFI, mean fluorescent intensity; PBD, p21-binding domain; RBD, Rho-binding domain; PAK-1, p21-activated kinase-1; RIU, relative intensity unit.