The experiments described thus far demonstrate the ability of PDE5 inhibition to prime/augment antitumor immunity. Yet the mechanisms resulting in T cell activation are unknown. Because PDE5 is expressed in various cells of the immune system (including DCs, macrophages, and T cells ), PDE5 inhibitors could putatively target these various populations. Furthermore, numerous factors are present in tumor-bearing hosts that could impair the generation of an effective immune response such as the defective maturation of DCs (7), the accumulation of suppressive MDSCs (4), T cell anergy (27), and/or the accumulation of T reg cells (28). These populations were, therefore, examined separately. Flow cytometric analysis of sildenafil-treated or untreated mice failed to reveal important differences in DC maturation, CD4+Foxp3+ T reg cells, or CD11b+/Gr-1+ MDSC accumulation (unpublished). We evaluated the effect of in vitro PDE5 inhibition on purified CD11c+, CD11b+, CD4+, and CD8+ cells isolated from C26GM tumor-bearing mice. This enabled us to examine purified populations, thereby eliminating the potential for exogenous influences. Although sildenafil treatment increased the intracellular concentration of cGMP in all the populations examined (Fig. 5 A), it had no effect on the proliferation of purified CD4+ and CD8+ T cells stimulated with either ConA (Fig. 5 B) or anti-CD3/CD28 beads (Fig. S5, available at http://www.jem.org/cgi/content/full/jem.20061104/DC1), nor on CD11c maturation (Fig. 5 C) as determined by B7.2 or MHC class II up-regulation. It did, however, demonstrate the ability to reverse the suppressive phenotype of MDSCs. In light of recent data identifying IL-4R as a functional suppressive marker for MDSCs (29), we examined IL-4R expression on CD11b+ cells cultured in the presence or absence of sildenafil. Fig. 5 D shows that sildenafil significantly decreases IL-4R expression on MDSCs, suggesting a down-regulation of their suppressive pathways.
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Potential Conflicts of Interest: Grants received: V. Snow (Bristol-Myers Squibb, Centers for Disease Control and Prevention, Novo Nordisk, Merck Vaccines, Boehringer Ingelheim, Wyeth, Sanofi Pasteur), P. Shekelle (Pfizer). Royalties: P. Shekelle (Up-to-Date). Any financial and nonfinancial conflict of interest of the group members were declared, discussed, and resolved.
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The arginase assay was performed as previously described (8) on purified intratumoral MDSCs.
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The experimental drug bremelanotide (formerly PT-141) does not act on the vascular system like the former compounds but allegedly increases sexual desire and drive in males as well as females. It is applied as a nasal spray. Bremelanotide allegedly works by activating melanocortin receptors in the brain. It is currently in Phase IIb trials.
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