Article

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

Sidney Kimmel Comprehensive Cancer Center, Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University, Baltimore, MD 21231, USA.
Journal of Experimental Medicine (Impact Factor: 13.21). 12/2006; 203(12):2691-702. DOI:10.1084/jem.20061104
Source: PubMed

ABSTRACT 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.

0 0
 · 
0 Bookmarks
 · 
92 Views
  • [show abstract] [hide abstract]
    ABSTRACT: Under many inflammatory contexts, such as tumor progression, systemic and peripheral immune response is tailored by reactive nitrogen species (RNS)-dependent post-translational modifications, suggesting a biological function for these chemical alterations. RNS modify both soluble factors and receptors essential to induce and maintain a tumor-specific immune response, creating a "chemical barrier" that impairs effector T cell infiltration and functionality in tumor microenvironment and supports the escape phase of cancer. RNS generation during tumor growth mainly depends on nitric oxide production by both tumor cells and tumor-infiltrating myeloid cells that constitutively activate essential metabolic pathways of l-arginine catabolism. This review provides an overview of the potential immunological and biological role of RNS-induced modifications and addresses new approaches targeting RNS either in search of novel biomarkers or to improve anti-cancer treatment.
    Frontiers in Immunology 01/2014; 5:69.
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: Since the beginning of the 20(th) century, scientists have tried to stimulate the anti-tumour activities of the immune system to fight against cancer. However, the scientific effort devoted on the development of cancer immunotherapy has not been translated into the expected clinical success. On the contrary, classical anti-neoplastic treatments such as surgery, radiotherapy and chemotherapy are the first line of treatment. Nevertheless, there is compelling evidence on the immunogenicity of cancer cells, and the capacity of the immune system to expand cancer-specific effector cytotoxic T cells. However, the effective activation of anti-cancer T cell responses strongly depends on efficient tumour antigen presentation from professional antigen presenting cells such as dendritic cells (DCs). Several strategies have been used to boost DC antigen presenting functions, but at the end cancer immunotherapy is not as effective as would be expected according to preclinical models. In this review we comment on these discrepancies, focusing our attention on the contribution of regulatory T cells and myeloid-derived suppressor cells to the lack of therapeutic success of DC-based cancer immunotherapy.
    New journal of science. 01/2014; 2014.
  • [show abstract] [hide abstract]
    ABSTRACT: Head and neck squamous cell carcinomas (HNSCCs) exhibit complex interactions with the host immune system that may simultaneously explain resistance to various therapeutic modalities and that may also provide opportunities for therapeutic intervention. Discoveries in immunologic research over the last decade have led to an increased understanding of these interactions as well as the development of a multitude of investigational immunotherapies. Here, we describe the interaction between HNSCC and the immune system, including a discussion of immune cells involved with tumor carcinogenesis and the role of immune-modulating factors derived from tumors. We also describe the current immunotherapeutic approaches being investigated for HNSCC, including a discussion of the successes and limitations. With this review, we hope to present HNSCC as a model to guide future research in cancer immunology.
    Immunologic Research 11/2013; · 2.96 Impact Factor

Full-text (2 Sources)

View
29 Downloads
Available from
Feb 16, 2013