The Journal of Experimental Medicine
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Published online 13 November 2006 doi:10.1084/jem.20061104
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 12, 2691-2702
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ARTICLE

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

Paolo Serafini1, Kristen Meckel1, Michael Kelso1, Kimberly Noonan1, Joseph Califano2, Wayne Koch2, Luigi Dolcetti3, Vincenzo Bronte3, and Ivan Borrello1

1 Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231
2 Department of Otolaryngology—Head and Neck Surgery, Johns Hopkins University, Baltimore, MD 21287
3 Istituto Oncologico Veneto, 35128 Padua, Italy

CORRESPONDENCE Ivan Borrello: borreiv{at}jhmi.edu

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.

Abbreviations used: ACT, adoptive cell therapy; ANOVA, analysis of variance; ARG1, arginase-1; CFSE, carboxyfluorescein diacetate succinimidyl ester; cGMP, cyclic guanosine monophosphate; HA, hemagglutinin; L-NMMA, NG-monomethyl-L-arginine; MDSC, myeloid-derived suppressor cell; MM, multiple myeloma; NorNOHA, N-(omega)-hydroxy-nor-L-arginine; NOS2, nitric oxide synthase–2; PBL, peripheral blood lymphocyte; PDE5, phosphodiesterase-5; TIL, tumor-infiltrating lymphocyte.


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