Phosphodiesterase-5 inhibition augments endogenous antitumor immunity by reducing myeloid-derived suppressor cell function

Paolo Serafini, Kristen Meckel, Michael Kelso, Kimberly Noonan, Joseph Califano, Wayne Martin Koch, Luigi Dolcetti, Vincenzo Bronte, Ivan M Borrello

Research output: Contribution to journalArticle

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 tumorspecific immune therapy. JEM

Original languageEnglish (US)
Pages (from-to)2691-2702
Number of pages12
JournalJournal of Experimental Medicine
Volume203
Issue number12
DOIs
StatePublished - Nov 2006

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Type 5 Cyclic Nucleotide Phosphodiesterases
Immunity
Phosphodiesterase 5 Inhibitors
Neoplasms
T-Lymphocytes
Tumor Escape
Arginase
Immunosuppressive Agents
Head and Neck Neoplasms
Cell- and Tissue-Based Therapy
Multiple Myeloma
Nitric Oxide Synthase
Immunosuppression
Blood Cells
Down-Regulation
Cell Proliferation
Myeloid-Derived Suppressor Cells
Sildenafil Citrate
Enzymes

ASJC Scopus subject areas

  • Immunology

Cite this

Phosphodiesterase-5 inhibition augments endogenous antitumor immunity by reducing myeloid-derived suppressor cell function. / Serafini, Paolo; Meckel, Kristen; Kelso, Michael; Noonan, Kimberly; Califano, Joseph; Koch, Wayne Martin; Dolcetti, Luigi; Bronte, Vincenzo; Borrello, Ivan M.

In: Journal of Experimental Medicine, Vol. 203, No. 12, 11.2006, p. 2691-2702.

Research output: Contribution to journalArticle

Serafini, Paolo ; Meckel, Kristen ; Kelso, Michael ; Noonan, Kimberly ; Califano, Joseph ; Koch, Wayne Martin ; Dolcetti, Luigi ; Bronte, Vincenzo ; Borrello, Ivan M. / Phosphodiesterase-5 inhibition augments endogenous antitumor immunity by reducing myeloid-derived suppressor cell function. In: Journal of Experimental Medicine. 2006 ; Vol. 203, No. 12. pp. 2691-2702.
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