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Tadalafil reduces myeloid-derived suppressor cells and regulatory T cells and promotes tumor immunity in patients with head and neck squamous cell carcinoma.

ABSTRACT: PURPOSE:Myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg) play a key role in the progression of head and neck squamous cell carcinoma (HNSCC). On the basis of our preclinical data demonstrating that phosphodiesterase-5 (PDE5) inhibition can modulate these cell populations, we evaluated whether the PDE5 inhibitor tadalafil can revert tumor-induced immunosuppression and promote tumor immunity in patients with HNSCC. EXPERIMENTAL DESIGN:First, we functionally and phenotypically characterized MDSCs in HNSCCs and determined, retrospectively, whether their presence at the tumor site correlates with recurrence. Then, we performed a prospective single-center, double-blinded, randomized, three-arm study in which patients with HNSCC undergoing definitive surgical resection of oral and oropharyngeal tumors were treated with tadalafil 10 mg/day, 20 mg/day, or placebo for at least 20 days preoperatively. Blood and tumor MDSC and Treg presence and CD8(+) T-cell reactivity to tumor antigens were evaluated before and after treatment. RESULTS:MDSCs were characterized in HNSCC and their intratumoral presence significantly correlates with recurrence. Tadalafil treatment was well tolerated and significantly reduced both MDSCs and Treg concentrations in the blood and in the tumor (P < 0.05). In addition, the concentration of blood CD8(+) T cells reactive to autologous tumor antigens significantly increased after treatment (P < 0.05). Tadalafil immunomodulatory activity was maximized at an intermediate dose but not at higher doses. Mechanistic analysis suggests a possible off-target effect on PDE11 at high dosages that, by increasing intracellular cAMP, may negatively affect antitumor immunity. CONCLUSIONS:Tadalafil seems to beneficially modulate the tumor micro- and macro-environment in patients with HNSCC by lowering MDSCs and Tregs and increasing tumor-specific CD8(+) T cells in a dose-dependent fashion.

SUBMITTER: Weed DT

PROVIDER: S-EPMC4322895 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Tadalafil reduces myeloid-derived suppressor cells and regulatory T cells and promotes tumor immunity in patients with head and neck squamous cell carcinoma.

Weed Donald T DT Vella Jennifer L JL Reis Isildinha M IM De la Fuente Adriana C AC Gomez Carmen C Sargi Zoukaa Z Nazarian Ronen R Califano Joseph J Borrello Ivan I Serafini Paolo P

Clinical cancer research : an official journal of the American Association for Cancer Research 20141015 1

<h4>Purpose</h4>Myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg) play a key role in the progression of head and neck squamous cell carcinoma (HNSCC). On the basis of our preclinical data demonstrating that phosphodiesterase-5 (PDE5) inhibition can modulate these cell populations, we evaluated whether the PDE5 inhibitor tadalafil can revert tumor-induced immunosuppression and promote tumor immunity in patients with HNSCC.<h4>Experimental design</h4>First, we functionally and ...[more]

PMID: 25320361

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Project description:BackgroundEcto-5'-nucleotidase (cluster of differentiation 73/CD73) is an ectonucleotidase that is being evaluated as a biomarker for the diagnosis and prognosis of various types of cancer. However, the clinicopathological relationship between CD73 expression in monocytic MDSCs (M-MDSCs) and polymorphonuclear MDSC (PMN-MDSCs) in head and neck squamous cell carcinomas (HNSCCs) is not clear. Understanding the phenotypic and functional characteristics of human CD73+ MDSCs in the tumor microenvironment could help elucidate the roles of these cells in the ontogeny, spread, and treatment of solid cancer.MethodsIn the present study, we first analyzed the expression percentage of human M-MDSCs and PMN-MDSCs subsets circulating in peripheral blood of patients with head and neck tumors originated in nasopharynx, oropharynx, oropharynx and larynx. To identify the correlation between phenotypic characteristics of MDSCs and clinical stages in HNSCC, we extended the study by analyzing the percentage, CD73 phenotype and immunosuppressive function of MDSCs and the correlation with the clinical parameters. Moreover, we compare the functions of both M-MDSCs and PMN-MDSCs blunts T-cell function in an ectonucleotidase-dependent manner.ResultsOur study revealed that PMN-MDSCs were significantly increased in HNSCC patients, contributing to MDSC-mediated T cell immune suppression. Our results indicated that PMN-MDSCs comprised the majority of MDSCs participating in anticancer immunosuppression. The increase in PMN-MDSCs was directly correlated with the clinical stages of HNSCC. Levels of CD73 were increased in PMN-MDSCs and were correlated with the clinical stages of HNSCC. The ectonucleotidase inhibitor adenosine 5'-(α,β-methylene)diphosphate (APCP) decreased its suppression towards T cell proliferation. Ectonucleotidase inhibitors are promising candidates for the treatment of HNSCC.ConclusionsThese studies demonstrate the expansion of PMN-MDSCs correlated with expression of CD73 and increasing clinical stages in HNSCC. These CD73+ PMN-MDSCs contributes to T cell immune suppression activity in HNSCC patients. Using ectonucleotidase inhibitors is a promising rationale for PMN-MDSCs in future clinical development of immunotherapy in human HNSCC cancer.

Project description:ObjectiveThis study is aimed at investigating the regulating mechanisms of the interferon regulatory factor (IRF) family genes in head and neck squamous cell carcinoma.MethodsBased on the HNSC data in the 'The Cancer Genome Atlas (TCGA)' database, the expression pattern of IRF family genes was investigated. The association of IRFs family genes and survival outcomes were analyzed by Kaplan-Meier plotter web portal. The relation of IRF genes and tumor stages was evaluated by using stage plots and based on GEPIA portal. 50 genes interacting with IRFs were identified using the NetworkAnalyst's protein-protein interaction (PPI) network construction tool. The top 200 correlated genes with similar expression patterns in HNSC were obtained by the similar gene detection module of GEPIA. Furthermore, functional enrichment analysis was performed to determine the biological functions enriched by the interacting and correlated genes. The potential implication of IRFs in tumor immunity was investigated in terms of tumor-infiltrating immune cells, a pair of immune checkpoint genes (CD274 and PDCD1), and ESTIMATE-Stromal-Immune score.ResultsThe unpaired sample analysis shows that all of the IRF family genes were highly expressed in HNSC tumor samples compared to control samples. The survival analysis results showed that the overexpression of IRF1, IRF4, IRF5, IRF6, IRF8, and IRF9 was associated with better overall survival in HNSC, while the other IRFs genes (IRF2, IRF3. and IRF7) did not show prognostic values for overall survival outcome of HNSC. Four genes (STAT1, STAT2, FOXP3, and SPI1) were overlapping among 50 interacted genes in the PPI network and top 200 correlated genes identified by GEPIA. The 50 interacting genes in the PPI network and top 200 correlated genes were integrated into 246 genes. These 246 genes were found to be overrepresented in multiple KEGG pathways, e.g., Th17 cell differentiation, T cell receptor signaling pathway, cytokine-cytokine receptor interaction, natural killer (NK) cell-mediated cytotoxicity, FOXO signaling, PI3K-Akt signaling, and ErbB signaling. Most correlations between IRF gene members and TIICs were positive. The strongest positive correlation was identified between IRF8 and T cells (r = 0.849, p < 0.001). The majority of correlation between IRF family genes and ESTIMATE-Stromal-Immune score was found to be positive. The highest positive correlation was found to be between IRF8 and Immune score (r = 0.874, p = 1.09E - 158). Most correlations between IRFs and two immunoinhibitor genes (CD274 and PDCD1) were positive. IRF1 and PDCD1 were found to show the highest positive correlation (r = 0.764, p < 2.2e - 16).ConclusionsThe current analysis showed IRFs were differentially expressed in HNSC, indicated significant prognostic values, were involved in tumor immunity-related signaling pathways, and significantly regulated tumor-infiltrating immune cells. IRF family genes could be potential therapeutic biomarkers in targeting tumor immunity of head and neck cancer.

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Tadalafil reduces myeloid-derived suppressor cells and regulatory T cells and promotes tumor immunity in patients with head and neck squamous cell carcinoma.

Publications

Tadalafil reduces myeloid-derived suppressor cells and regulatory T cells and promotes tumor immunity in patients with head and neck squamous cell carcinoma.

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