Ciaglia, Elena (2009) The crosstalk between Dendritic and Natural Killer cells together with the function of Tumor Associated Macrophages (TAM) represent novel cancer-related targets for Human Immunodeficiency Type-1 Protease Inhibitors. [Tesi di dottorato] (Unpublished)

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Inflammatory conditions and infections in selected organs increase the risk of cancer. In the tumor microenvironment, smoldering inflammation contributes to proliferation and survival of malignant cells, angiogenesis, metastasis and subversion of adaptive immunity. The human immunodeficiency virus (HIV) infection is characterized by increased risk of several solid tumors due to its inherent nature of weakening the immune system. Recent observations point to a lower incidence of some cancers in patients treated with protease inhibitor (PI) cocktail such as HAART (Highly Active Anti-Retroviral Therapy). Human Immunodeficiency Type-1 Virus protease inhibitors (HIV-1-PIs) originally designed to block selectively the aspartic protease of HIV-1, also shown the ability to modulate a variety of biological functions, including the immune response, by mechanisms largely independent from their anti-viral activity. Herein, we investigate the effects of PIs on differentiation programs of monocytes toward: (a) dendritic cells (DC); (b) Tumor Associated Macrophages-like cells (TAM-like). Differentiation of human circulating monocytes in the presence of PIs led to generation of DC with atypical phenotype, including low level of Cd1a, and DC-SIGN, a receptor that enables DC to bind HIV-1 virions in tissues, and carry them to lymphonodes. Moreover, DC generated in the presence of ritonavir also fail to terminally differentiate, and secrete lower amounts of IL- 12 and IL-15, in response to bacterial endotoxin (LPS). This phenomenon parallels their inability to prime NK cells, and become resistant to NK-mediated cytotoxicity. The exposure of monocytes to certains PIs determines generation of Tumour Associated Macrophages-Like cells with an atypical phenotype, including higher level of the co-stimulatory molecules CD86, and lower expression of ILT3, a receptor playing an imunosuppressive role. Accordingly, in response to LPS, TAM-like cells generated in the presence of PIs, secrete lower amount of MM9 and VEGF, a phenomenon accompanying their ability to release more GM-CSF. Altogether, these findings demonstrate the ability of PIs to modulate the differentiation programs of human monocytes. The remakable property of certain PIs to modulate phenotypes and functionalities of DC and TAM, might open novel perspectives for immune-intervention aimed to manipulate the cancer inflammatory milieu.

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