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Altered Expression of 15-Hydroxyprostaglandin Dehydrogenase in Tumor-Infiltrated CD11b Myeloid Cells: A Mechanism for Immune Evasion in Cancer

Evgeniy Eruslanov^*, Sergei Kaliberov, Irina Daurkin^*, Lyudmila Kaliberova, Donald Buchsbaum, Johannes Vieweg^* and Sergei Kusmartsev^1,*

^* Department of Urology and Shands Cancer Center, University of Florida, College of Medicine, Gainesville, FL 32610; and Department of Radiation Oncology, University of Alabama, Birmingham, AL 35294

Many cancers are known to produce high amounts of PGE₂, which is involved in both tumor progression and tumor-induced immune dysfunction. The key enzyme responsible for the biological inactivation of PGE₂ in tissue is NAD⁺-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH). It is well established that cancer cells frequently show down-regulated expression of 15-PGDH, which plays a major role in catabolism of the PGE₂. Here we demonstrate that tumor-infiltrated CD11b cells are also deficient for the 15-PGDH gene. Targeted adenovirus-mediated delivery of 15-PGDH gene resulted in substantial inhibition of tumor growth in mice with implanted CT-26 colon carcinomas. PGDH-mediated antitumor effect was associated with attenuated tumor-induced immune suppression and substantially reduced secretion of immunosuppressive mediators and cytokines such as PGE₂, IL-10, IL-13, and IL-6 by intratumoral CD11b cells. We show also that introduction of 15-PGDH gene in tumor tissue is sufficient to redirect the differentiation of intratumoral CD11b cells from immunosuppressive M2-oriented F4/80⁺ tumor-associated macrophages (TAM) into M1-oriented CD11c⁺ MHC class II-positive myeloid APCs. Notably, the administration of the 15-PGDH gene alone demonstrated a significant therapeutic effect promoting tumor eradication and long-term survival in 70% of mice with preestablished tumors. Surviving mice acquired antitumor T cell-mediated immune response. This study for the first time demonstrates an important role of the 15-PGDH in regulation of local antitumor immune response and highlights the potential to be implemented to enhance the efficacy of cancer therapy and immunotherapy.

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 Address correspondence and reprint requests to Dr. Sergei Kusmartsev, Cancer and Genetics Research Center, University of Florida, 1376 Mowry Road, Room 459, P.O. Box 103633, Gainesville, FL 32610. E-mail address: s.kusmartsev{at}urology.ufl.edu

² Abbreviations used in this paper: COX-2, cyclooxygenase-2; 15-PGDH, 15-hydroxyprostaglandin dehydrogenase; MDSC, myeloid-derived suppressor cell; TAM, tumor-associated macrophage; TCID₅₀, 50% tissue culture infectious dose; VEFG, vascular endothelial growth factor.

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