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

Donald Weed, Jennifer L. Vella, Isildinha Reis, Adriana C. De La Fuente, Carmen Gomez-Fernandez, Zoukaa B Sargi, Ronen Nazarian, Joseph Califano, Ivan Borrello, Paolo Serafini

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)39-48
Number of pages10
JournalClinical Cancer Research
Volume21
Issue number1
DOIs
StatePublished - Jan 1 2015

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Immunity
Neoplasms
Neoplasm Antigens
T-Lymphocytes
Type 5 Cyclic Nucleotide Phosphodiesterases
Phosphodiesterase 5 Inhibitors
Recurrence
Myeloid-Derived Suppressor Cells
Tadalafil
Carcinoma, squamous cell of head and neck
Autoantigens
Regulatory T-Lymphocytes
Immunosuppression
Research Design
Therapeutics
Placebos
Population

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

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; Vella, Jennifer L.; Reis, Isildinha; De La Fuente, Adriana C.; Gomez-Fernandez, Carmen; Sargi, Zoukaa B; Nazarian, Ronen; Califano, Joseph; Borrello, Ivan; Serafini, Paolo.

In: Clinical Cancer Research, Vol. 21, No. 1, 01.01.2015, p. 39-48.

Research output: Contribution to journalArticle

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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.",
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T1 - Tadalafil reduces myeloid-derived suppressor cells and regulatory t cells and promotes tumor immunity in patients with head and neck squamous cell carcinoma

AU - Weed, Donald

AU - Vella, Jennifer L.

AU - Reis, Isildinha

AU - De La Fuente, Adriana C.

AU - Gomez-Fernandez, Carmen

AU - Sargi, Zoukaa B

AU - Nazarian, Ronen

AU - Califano, Joseph

AU - Borrello, Ivan

AU - Serafini, Paolo

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AB - 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.

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