NSU-MD Faculty Articles

Altered expression of 15-hydroxyprostaglandin dehydrogenase in tumor-infiltrated CD11b myeloid cells: a mechanism for immune evasion in cancer.

Publication Title

Journal of immunology

Publisher

American Association of Immunologists

ISSN

0022-1767

Publication Date

6-15-2009

Keywords

Adenoviridae, Animals, Antigen-Presenting Cells, CD11b Antigen, Cell Differentiation, Cell Line, Tumor, Cytokines, Dinoprostone, Disease Models, Animal, Female, Gene Expression Regulation, Enzymologic, Humans, Hydroxyprostaglandin Dehydrogenases, Lymph Nodes, Male, Mice, Myeloid Cells, Neoplasm Transplantation, Neoplasms, Survival Rate, Tumor Escape

Abstract

Many cancers are known to produce high amounts of PGE(2), which is involved in both tumor progression and tumor-induced immune dysfunction. The key enzyme responsible for the biological inactivation of PGE(2) 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 PGE(2). 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 PGE(2), 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.

DOI

10.4049/jimmunol.0802358

Volume

182

Issue

12

First Page

7548

Last Page

7557

Disciplines

Medicine and Health Sciences

Link to Full Text
Peer Reviewed

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