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PMID:17101732

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Citation

Serafini, P, Meckel, K, Kelso, M, Noonan, K, Califano, J, Koch, W, Dolcetti, L, Bronte, V and Borrello, I (2006) Phosphodiesterase-5 inhibition augments endogenous antitumor immunity by reducing myeloid-derived suppressor cell function. J. Exp. Med. 203:2691-702

Abstract

Phosphodiesterase-5 (PDE5) inhibitors (sildenafil, tadalafil, and vardenafil) are agents currently in clinical use for nonmalignant conditions. We report the use of PDE5 inhibitors as modulators of the antitumor immune response. In several mouse tumor models, PDE5 inhibition reverses tumor-induced immunosuppressive mechanisms and enables a measurable antitumor immune response to be generated that substantially delays tumor progression. In particular, sildenafil, down-regulates arginase 1 and nitric oxide synthase-2 expression, thereby reducing the suppressive machinery of CD11b+/Gr-1+ myeloid-derived suppressor cells (MDSCs) recruited by growing tumors. By removing these tumor escape mechanisms, sildenafil enhances intratumoral T cell infiltration and activation, reduces tumor outgrowth, and improves the antitumor efficacy of adoptive T cell therapy. Sildenafil also restores in vitro T cell proliferation of peripheral blood mononuclear cells from multiple myeloma and head and neck cancer patients. In light of the recent data that enzymes mediating MDSC-dependent immunosuppression in mice are active also in humans, these findings demonstrate a potentially novel use of PDE5 inhibitors as adjuncts to tumor-specific immune therapy.

Links

PubMed PMC2118163 Online version:10.1084/jem.20061104

Keywords

3',5'-Cyclic-GMP Phosphodiesterases/antagonists & inhibitors; 3',5'-Cyclic-GMP Phosphodiesterases/physiology; Animals; Antineoplastic Agents/pharmacology; CD8-Positive T-Lymphocytes/drug effects; CD8-Positive T-Lymphocytes/immunology; CD8-Positive T-Lymphocytes/pathology; Cell Differentiation/immunology; Cell Line, Tumor; Cyclic Nucleotide Phosphodiesterases, Type 5; Melanoma, Experimental/enzymology; Melanoma, Experimental/immunology; Melanoma, Experimental/prevention & control; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Myeloid Cells/cytology; Myeloid Cells/immunology; Neoplasms/enzymology; Neoplasms/immunology; Neoplasms/prevention & control; Phosphodiesterase Inhibitors/pharmacology; T-Lymphocytes, Regulatory/enzymology; T-Lymphocytes, Regulatory/immunology

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:PDE5A

acts_upstream_of_or_within

GO:0042130: negative regulation of T cell proliferation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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