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

By P. Serafini, Kristen F. Meckel, M. Kelso, K. Noonan, J. Califano, W. Koch, L. Dolcetti, V. Bronte, I. Borrello. Journal of Experimental Medicine, 2006

770 citations recorded by the source corpus.

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.

Subfields: Immunology, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/c8b90035380bbe333758ba2dd89de71a39ed00bf

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Citations in the corpus

Arginine regulation by myeloid derived suppressor cells and tolerance in cancer: mechanisms and therapeutic perspectives (2008, methodology): “Multiple approaches have been taken to block MDSC suppression using alltransretinoic acid (130), inhibiting nitric oxide function with nitro-aspirin (136), inhibiting phosphodiesterase-5 (137), and blocking arginase activity with specific arginase inhibitors such as Nor-NOHA (98).”
Radiation-induced CXCL16 release by breast cancer cells attracts effector T cells (2008, methodology): “The 4T1, 4T07, 66cl4, 168FARN, and 67NR BALB/c mouse-derived mammary carcinoma cell lines (26) and 4T1-HA derivatives (30), were grown in DMEM (Invitrogen) supplemented with 2 mM L-glutamine, 100 U/ml penicillin, 100 g/ml streptomycin, 2.”
Tumor-induced tolerance and immune suppression depend on the C/EBPbeta transcription factor. (2010, background): “Since Nos2 is pivotal in MDSC-induced suppression in C57BL/6 mice (Mazzoni et al., 2002; Serafini et al., 2006), we compared the in vitro inhibitory activity of CD11b+ splenocytes from tumor-bearing mice (spleen MDSCs) and BM-MDSCs from either wild-type or Nos2 ablated mice.”
Myeloid derived suppressor cells (2013, background): “Serafini et al.(65) demonstrated that sildenafil treatment restored T-cell proliferation in PBMCs from patients with head and neck squamous cell carcinoma (HNSCC) and multiple myeloma, suggesting that the therapeutic effect observed in mice can be translated into treatment of human cancer.”
Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, and doxorubicin–cyclophosphamide chemotherapy (2008, background): “Promising agents have been studied in mice, including alltrans retinoic acid, celecoxib, and phosphodiesterase-5 inhibitors, that decrease MDSC numbers or blunt their immunosuppressive properties on T cells [1, 27, 29].”
Myeloid-derived suppressor cell heterogeneity and subset definition. (2010, background): “MDSCs with similar phenotype were also observed among PBMCs isolated from prostate cancer patients [37], and CD14 human MDSCs susceptible to phosphopdiesterase 5 inhibitors were described in multiple myeloma and head and neck cancer patients [38].”
Myeloid derived suppressor cells promote cross-tolerance in B cell lymphoma by expanding regulatory T cells (2008, background): “Because most MDSC suppressive pathways can be inhibited by down-regulating IL4Ra (17, 22, 28, 29), we asked if sildenafil could also reverse tumor-induced T-cell anergy and Treg proliferation.”
Coordinated regulation of myeloid cells by tumours (2012, background): “, whereas CD14 + CD11b + HLA-DR low/− monocytic MDSCs circulate in the blood of patients with melanoma, multiple myeloma, prostate cancer, hepatocellular carcinoma or head and neck cance”
Arginase: an emerging key player in the mammalian immune system (2009, background): “MDSC can suppress T cell immune functions by constitutive expression of arginase with consecutive L-arginine depletion (Bronte et al., 2003; Liu et al., 2003; Kusmartsev et al., 2004; Rodriguez et al., 2004; Sinha et al., 2005; Gallina et al., 2006; Serafini et al., 2006b).”