Depletion of Dendritic Cells Delays Ovarian Cancer Progression by Boosting Antitumor Immunity

¹ Departments of ¹Microbiology and Immunology, ²Pathology, and ³Medicine, Dartmouth Medical School, Lebanon, New Hampshire; Departments of ⁴Internal Medicine and ⁵Obstetrics and Gynecology, University of Michigan, Ann Arbor, Michigan; ⁶Department of Biomedical Sciences, Ohio University, Athens, Ohio; ⁷Celldex Therapeutics, Phillipsburg, New Jersey; and ⁸Center for Applied Medical Research, University of Navarra, Pamplona, Navarra, Spain

^* To whom correspondence should be addressed. E-mail: Jose.R.Conejo-Garcia{at}Dartmouth.edu.

	Abstract

Dendritic cells (DC) and cytokines that expand myeloid progenitors are widely used to treat cancer. Here, we show that CD11c⁺DEC205⁺ DCs coexpressing -smooth muscle actin and VE-cadherin home to perivascular areas in the ovarian cancer microenvironment and are required for the maintenance of tumor vasculature. Consequently, depletion of DCs in mice bearing established ovarian cancer by targeting different specific markers significantly delays tumor growth and enhances the effect of standard chemotherapies. Tumor growth restriction was associated with vascular apoptosis after DC ablation followed by necrosis, which triggered an antitumor immunogenic boost. Our findings provide a mechanistic rationale for selectively eliminating tumor-associated leukocytes to promote antitumor immunity while impeding tumor vascularization and to develop more effective DC vaccines based on a better understanding of the tumor microenvironment. [Cancer Res 2008;68(18):7684–91]

Key Words: immunotherapy, tumor immune evasion, tumor microenvironment

This article has been cited by other articles:

				U. K. Scarlett, J. R. Cubillos-Ruiz, Y. C. Nesbeth, D. G. Martinez, X. Engle, A. T. Gewirtz, C. L. Ahonen, and J. R. Conejo-Garcia In situ Stimulation of CD40 and Toll-like Receptor 3 Transforms Ovarian Cancer-Infiltrating Dendritic Cells from Immunosuppressive to Immunostimulatory Cells Cancer Res., September 15, 2009; 69(18): 7329 - 7337. [Abstract] [Full Text] [PDF]

				A. Barber and C. L. Sentman Chimeric NKG2D T Cells Require Both T Cell- and Host-Derived Cytokine Secretion and Perforin Expression to Increase Tumor Antigen Presentation and Systemic Immunity J. Immunol., August 15, 2009; 183(4): 2365 - 2372. [Abstract] [Full Text] [PDF]

				Y. Nesbeth, U. Scarlett, J. Cubillos-Ruiz, D. Martinez, X. Engle, M.-J. Turk, and J. R. Conejo-Garcia CCL5-Mediated Endogenous Antitumor Immunity Elicited by Adoptively Transferred Lymphocytes and Dendritic Cell Depletion Cancer Res., August 1, 2009; 69(15): 6331 - 6338. [Abstract] [Full Text] [PDF]