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Tadalafil augments tumor specific immunity in patients with head and neck squamous cell carcinoma.

ABSTRACT: PURPOSE:To determine if phosphodiesterase 5 (PDE5) inhibitors can augment immune function in patients with head and neck cancer through inhibition of myeloid-derived suppressor cells (MDSC). EXPERIMENTAL DESIGN:We performed a randomized, prospective, double blinded, placebo controlled, phase II clinical trial to determine the in vivo effects of systemic PDE5 inhibition on immune function in patients with head and neck squamous cell carcinoma (HNSCC). RESULTS:Tadalafil augmented immune response, increasing ex vivo T-cell expansion to a mean 2.4-fold increase compared with 1.1-fold in control patients (P = 0.01), reducing peripheral MDSC numbers to mean 0.81-fold change compared with a 1.26-fold change in control patients (P = 0.001), and increasing general immunity as measured by delayed type hypersensitivity response (P = 0.002). Tumor-specific immunity in response to HNSCC tumor lysate was augmented in tadalafil-treated patients (P = 0.04). CONCLUSIONS:These findings demonstrate that tadalafil augments general and tumor-specific immunity in patients with HNSCC and has therapeutic potential in HNSCC. Evasion of immune surveillance and suppression of systemic and tumor-specific immunity is a significant feature of head and neck cancer development. This study demonstrates that a PDE5 inhibitor, tadalafil, can reverse tumor-specific immune suppression in patients with head and neck cancer, with potential for therapeutic application.

SUBMITTER: Califano JA

PROVIDER: S-EPMC4329916 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Tadalafil augments tumor specific immunity in patients with head and neck squamous cell carcinoma.

Califano Joseph A JA Khan Zubair Z Noonan Kimberly A KA Rudraraju Lakshmi L Zhang Zhe Z Wang Hao H Goodman Steven S Gourin Christine G CG Ha Patrick K PK Fakhry Carole C Saunders John J Levine Marshall M Tang Mei M Neuner Geoffrey G Richmon Jeremy D JD Blanco Ray R Agrawal Nishant N Koch Wayne M WM Marur Shanthi S Weed Donald T DT Serafini Paolo P Borrello Ivan I

Clinical cancer research : an official journal of the American Association for Cancer Research 20150101 1

<h4>Purpose</h4>To determine if phosphodiesterase 5 (PDE5) inhibitors can augment immune function in patients with head and neck cancer through inhibition of myeloid-derived suppressor cells (MDSC).<h4>Experimental design</h4>We performed a randomized, prospective, double blinded, placebo controlled, phase II clinical trial to determine the in vivo effects of systemic PDE5 inhibition on immune function in patients with head and neck squamous cell carcinoma (HNSCC).<h4>Results</h4>Tadalafil augme ...[more]

PMID: 25564570

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Project description:Head and neck squamous cell carcinoma (HNSCC) is a deadly and disfiguring disease for which better systemic therapy is desperately needed. The development of new therapies for HNSCC and the understanding of its biology both depend upon clinically relevant animal models. An increasingly promising xenograft model, the patient derived xenograft (PDX), is developed by surgically implanting tumor tissue directly from a patient into an immunocompromised mouse. We transplanted 30 HNSCC primary tumors directly into mice. The histology and stromal components were analyzed using immunohistochemistry. Gene expression analysis with Affymetrix U133A-microarrays was conducted on patient tumors, including third generation and one tenth generation PDX; one PDX-derived cell line; and 2 established HNSCC cell lines. Five of 30 (17%) transplanted tumors could be serially passaged and used for therapeutic and mechanistic studies. One cell line has been established from a tongue primary. The tumors maintained the histologic appearance of the parent tumor although human stromal components were lost upon engraftment. One PDX model was derived from an HPV-positive tumor. From the >54,000 probes tested, there were widespread differences in gene expression between the tumors growing in mice vs. the corresponding human tumors from which they were derived. For genes differing between parent tumors and human cell lines in culture, the PDXs’ expression pattern was very similar to that of the parent tumors. There were also widespread expression differences between the human tumors that subsequently grew in mice vs. those that did not - suggesting that this model enriches for cancers with distinct biological features. Our results demonstrate the feasibility of a PDX model of HNSCC. Gene expression patterns suggest that the PDX more closely recapitulated the parental tumor than do cells in culture. The histology of the tumors in mice is similar to that of the same tumor in humans. Additionally, gene expression patterns and histology are stable over multiple generations.

Dataset Information

Tadalafil augments tumor specific immunity in patients with head and neck squamous cell carcinoma.

Publications

Tadalafil augments tumor specific immunity in patients with head and neck squamous cell carcinoma.

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