Serafini, P. et al. Phosphodiesterase-5 inhibition augments endogenous antitumor immunity by reducing myeloid-derived suppressor cell function. J. Exp. Med. 203, 2691-2702

Sidney Kimmel Comprehensive Cancer Center, Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University, Baltimore, MD 21231, USA.
Journal of Experimental Medicine (Impact Factor: 12.52). 12/2006; 203(12):2691-702. DOI: 10.1084/jem.20061104
Source: PubMed


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.

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    • "ROS and peroxynitrite inhibit CD8 + T cells by catalyzing the nitration of the TCR and preventing T cell–peptide–MHC interactions essential for CD8 + activation (Wiers et al., 2000). MDSCs have thus emerged as a potential target in cancer immunotherapeutics with triterpenoids (Thimmulappa et al., 2007), arginase (Serafini et al., 2008), cyclooxygenase 2 (Sinha et al., 2007), phosphodiesterase-5 inhibitors (Serafini et al., 2006), and nitroaspirin (Nagaraj et al., 2010; Molon et al., 2011; Mundy-Bosse et al., 2011) as promising inhibitors of MDSC metabolism and expression. "
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    • "It enhanced intratumoral T-cell infiltration and activation, reduced tumor outgrowth, and improved the antitumor efficacy of adoptive T-cell therapy. Furthermore, sildenafil restored T-cell proliferation of peripheral blood mononuclear cells from multiple myeloma and head and neck cancer patients in vitro [62]. It is not clear whether this favorable effect will be observed clinically in cancer patients. "
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