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Randomized Controlled Trial
. 2015 Jan 1;21(1):39-48.
doi: 10.1158/1078-0432.CCR-14-1711. Epub 2014 Oct 15.

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

Donald T Weed #  1 , Jennifer L Vella  2 , Isildinha M Reis  3 , Adriana C De la Fuente  2 , Carmen Gomez  4 , Zoukaa Sargi  1 , Ronen Nazarian  1 , Joseph Califano  5   6 , Ivan Borrello  7 , Paolo Serafini #  2
Affiliations
Randomized Controlled Trial

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

Donald T Weed et al. Clin Cancer Res. .

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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Figures

Figure 1
Figure 1
Consolidated standards of reporting trials (CONSORT) diagram.
Figure 2
Figure 2
MDSCs identification. A, the indicated myeloid cell subsets were tested for suppressive activity against CFSE-labeled autologous T cells stimulated with beads coated with anti-CD3/anti-CD28 antibodies. Data normalized on the control (no MDSC) are cumulative of five independent experiments using PBMCs from 5 patients. P value for the ANOVA test (Pa) and the Tukey post hoc test are reported. B, example of multicolor FACS analysis for MDSC phenotype CD33+IL4Rα+ cells are highlighted in blue. C, intratumoral CD33+ IL4Rα+ cells were retrospectively evaluated in the tumor specimen of recurrent or nonrecurrent OSCC patients by immunofluorescence microscopy. P value for t test is reported.
Figure 3
Figure 3
Tadalafil reduces MDSCs and Treg. MDSCs (A) and Treg (B) concentration was evaluated in patients PBMCs before (t1), after tadalafil treatment (t2), and 6 weeks after surgery (t3). Pw, Wilcoxon signed-rank test; Pt, paired t test.
Figure 4
Figure 4
Tadalafil increases antitumor immunity. T cells from PBMCs drawn at t1, t2, or t3 were stimulated with monocytes-derived autologous DC pulsed with autologous tumor. Four days later, CD8+ T-cell proliferation was evaluated by FACS. Background from parallel culture using unpulsed DC was subtracted. Pw, Wilcoxon signed-rank test; Pt, paired t test.
Figure 5
Figure 5
An intermediate tadalafil dose modulates most effectively tumor immunity. The ratio between the MDSCs (A) or the log2-ratio of the CD8 proliferation (B) after (t2) and before (t1) pharmacologic treatment was plotted against the weight-normalized tadalafil dose. Best-fitting quadratic curve and confidence interval (gray area) are reported. cGMP (C) and cAMP (D) were measured by ELISA in the following FACS-sorted cell population from patients (n = 3) treated with intermediate or high dosage of tadalafil: CD33+IL4Rα+ (MDSCs), HLADRhigh (APC), or CD3+ (T cells). Pt, paired t test; BDL, below detection limit.
Figure 6
Figure 6
Tadalafil modulates tumor microenvironment. CD33/IL4Rα (A), CD4/FoxP3 (B), or CD8/CD69 (C) intratumoral concentration was evaluated by immune-fluorescence microscopy. Pa, P ANOVA test.
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