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

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