Phosphodiesterase-5 inhibition augments endogenous antitumor immunity by reducing myeloid-derived suppressor cell function.
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.
Serafini
Paolo
P
Sidney Kimmel Comprehensive Cancer Center, Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University, Baltimore, MD 21231, USA.
Meckel
Kristen
K
Kelso
Michael
M
Noonan
Kimberly
K
Califano
Joseph
J
Koch
Wayne
W
Dolcetti
Luigi
L
Bronte
Vincenzo
V
Borrello
Ivan
I
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000502:physiology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D002454:Cell Differentiation / Q000276:immunology; D045744:Cell Line, Tumor; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D008546:Melanoma, Experimental / Q000201:enzymology / Q000276:immunology / Q000517:prevention & control; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000166:cytology* / Q000276:immunology; D009369:Neoplasms / Q000201:enzymology* / Q000276:immunology / Q000517:prevention & control*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D050378:T-Lymphocytes, Regulatory / Q000201:enzymology* / Q000276:immunology*
D000970:Antineoplastic Agents; D010726:Phosphodiesterase Inhibitors; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517382:Pde5a protein, mouse