Giovanni Sitia
Giovanni Sitia
affiliation: San Raffaele Scientific Institute
research area(s): Immunity And Infection, Experimental Medicine
  • Cell and Molecular Biology
  • Basic and Applied Immunology
University/Istitution: Università Vita-Salute San Raffaele
1997 MD in Medicine and Surgery, University of Milan, 100/110.
2001-2004 Residency and Board certified in Infectious Disease, Vita-Salute San Raffaele University, School of Medicine, Milan, 70/70 cum laude.

Research and professional experience:
2001-2003 Research fellow in the Laboratory of Prof. Luca Guidotti,
Department of Molecular and Experimental Medicine
The Scripps Research Institute, La Jolla, CA, USA.
2004-2005 Research fellow in the Laboratory of Prof. Marco Bianchi,
Chromatin Dynamics Unit, DIBIT, San Raffaele Scientific Institute, Milan, Italy.
2004-2006 Research fellow in the Laboratory of Prof. Luca Guidotti,
Immunopathogenesis of Liver Infections Unit, DIBIT, San Raffaele Scientific Institute, Milan, Italy.
2007-2010 Scientist in the Laboratory of Prof. Luca Guidotti, Immunopathogy Unit, DIBIT, San Raffaele Scientific Institute, Milan, Italy.
2008 Visiting Scientist, Department of Gastroenterology, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan.
2010-Present Group Leader in the Immunopathogy Unit, Division of Immunology, San Raffaele Scientific Institute, Milan, Italy.
Primary liver cancer (HCC) is the result of many years of chronic liver infections (HBV and HCV), which are characterized by continuous cycles of low-level liver cell destruction caused by a dysfunctional and detrimental virus-specific cytotoxic T lymphocyte (CTL) response that is unable to completely clear HBV or HCV from the liver. Our program aims to identify cellular and molecular pathways required for multistep transformation process and to set up and explore new possible therapeutic strategies for the treatment of this disease. These innovative approaches include the modulation of immune mechanisms counteracting anti-tumor immune responses and the targeted delivery of anti tumor drugs.
1. Sitia G., M. Isogawa, K. Kakimi, S.F. Wieland, F.V. Chisari, and L.G. Guidotti. Depletion of neutrophils blocks the recruitment of antigen-nonspecific cells into the liver without affecting the antiviral activity of hepatitis B virus-specific cytotoxic T lymphocytes. Proc Natl Acad Sci USA 99:13717-13722. 2002.
2. Sitia G., M. Isogawa, M. Iannacone, IL. Campbell, F.V. Chisari, and L.G. Guidotti. MMPs Are Required For the Recruitment of Antigen-Nonspecific Mononuclear Cells Into the Liver by CTLs. J Clin Invest: 113:1158-1167. 2004.
3. Iannacone M, G. Sitia, M Isogawa, P Marchese, MG. Castro, PR. Lowenstein, FV. Chisari, ZM. Ruggeri and LG Guidotti. Platelets mediate cytotoxic T lymphocyte-induced liver damage in the liver. Nat Med. 11:1167-9. 2005.
4. Sitia G, De Bona A, Bagaglio S, Paties C, Uberti-Foppa C, Guidotti LG, Lazzarin A and Morsica G. Naïve HIV/HCV Co-Infected Patients Have Higher Intrahepatic Pro-Inflammatory Cytokines than Co-Infected Patients Treated with Antiretroviral. Antivir Ther. 11:385-389. 2006
5. Sitia G*, Brown BD*, Annoni A, Hauben H, Sergi Sergi L, Zingale A, Roncarolo MG, Guidotti LG, Naldini L. In Vivo Administration of Lentiviral Vectors Triggers a Type I Interferon Response That Restricts Hepatocyte Gene Transfer and Promotes Vector Clearance. *equal contribution. Blood, 109:2797-2805, 2007
6. Sitia G, Iannacone M, Mülle S, Bianchi ME, Guidotti LG. Treatment with HMGB1 Inhibitors Diminishes CTL-induced Liver Disease in HBV Transgenic Mice. J Leukoc Biol 81:100-107, 2007
7. Iannacone M, Sitia G, Isogawa M, Whitmire JK, Marchese P, Chisari FV, Ruggeri ZM, Guidotti LG. Platelets prevent IFN-α/β-induced lethal hemorrhage promoting CTL-dependent clearance of lymphocytic choriomeningitis virus. PNAS 15;105: 629-34. 2008
8. De Palma M, Mazzieri R, Politi LS, Pucci F, Zonari E, Sitia G, Mazzoleni S, Moi D, Venneri MA, Idraccolo S, Falini A, Guidotti LG, Galli R, Naldini L. Tumor-Targeted Interferon-α Delivery by Tie2-Expressing Monocytes Inhibits Tumor Growth and Metastasis. Cancer Cell 14; 299-311 2008
9. Tomasoni R, Basso V, Pilipow K, Sitia G, Saccani S, Agresti A, Mietton F, Natoli G, Colombetti S, Mondino A. Rapamycin-sensitive signals control TCR/CD28-driven Ifng, Il4 and Foxp3 transcription and promoter region methylation. Eur J Immunol. 2011 Apr 8. doi: 10.1002/eji.201041130. [Epub ahead of print]
10. Sitia G, Iannacone M, Aiolfi R, Isogawa M, van Rooijen N, Scozzesi C, Bianchi ME, von Andrian U, Chisari FV, Guidotti LG. Kupffer cells hasten resolution of liver immunopathology in mouse models of viral hepatitis. PLoS Pathog 7(6): e1002061. doi:10.1371/journal.ppat.1002061. Epub 2011 Jun 2.
Project Title:
Modulation of immune mechanisms counteracting anti-tumor immune responses in mouse models of HCC
We will use the mouse model of chronic hepatitis and HCC that we previously described, that consists of HBV transgenic mice (lineage 107-5) whose hepatocytes express the HBsAg-containing large, middle and small envelope proteins of HBV. 107-5 mice are immunologically tolerant to HBsAg and spontaneously develop neither hepatitis nor HCC, unless their immune system is replaced with that of syngeneic nontransgenic mice immunized with HBsAg. By so doing the animals acquire a persistent, low degree immune-mediated liver disease that over many months triggers the development of multifocal HCCs (1-3). To identify HCCs potentially treatable by RFA (radio frequency thermal ablation) we will employ a 7.0T magnetic field scanner. HCCs developed in the left liver lobe will be subjected to RFA (the most widely used treatment for HCC). Thermal ablation is a curative approach for HCC that, unfortunately, has a high rate of disease recurrence owing to the typical multifocal origin of this cancer and the frequent intrahepatic metastasis (4, 5). For these reasons we will attempt to develop immunological therapies aimed at boosting tumor-specific T cell responses by combining thermal ablation to the local delivery of syngenic dendridic cells with or without reagents that may favor the in-vivo priming or overcome anti-tumor CTL exhaustion.

Project Title:
Define the role of myeloid cells in the induction and progression of hepatocellular carcinoma.
We will take advantage of the HBV transgenic mice (lineage 107-5) that develop a mild but persistent HBV-specific CTL response (similar to that of chronically infected patients) upon replacement of their tolerant immune system with a non-tolerant one (1-3). This CTL response sustains a low-degree chronic necroinflammatory liver disease characterized by periportal infiltration of inflammatory cells and Kupffer cell hyperplasia very similar to what observed in humans. We will use immunological techniques to characterize the cellular composition of periportal lesions using both Facs analysis, confocal fluorescent microscopy and liver pathology and state-of the art 2-P intravital microscopy. In particular we will characterize the myeloid compartment of inflammatory cells with pro-angiogenic and pro-tumor features that have been identified both in mice and humans that might have an important role also in the development and progression of HCC. We will test whether Tie2-expressing monocytes (genetically engineered to carry fluorescent proteins) home to preneoplastic hepatomas, or to established HCCs in 107-5 mice, in order to define their role in the pathogenesis of HCC (4). These studies will be of paramount importance to establish weather Tie-2 expressing monocytes may be used to deliver anticancer drugs to established HCCs as very recently shown to effectively occur in other tumors in mice.

1. Guidotti, L.G. and F.V. Chisari, Immunobiology and pathogenesis of viral hepatitis. Annu Rev Pathol, 2006. 1: p. 23-61.
2. Sitia, G., et al., Kupffer cells hasten resolution of liver immunopathology in mouse models of viral hepatitis. PLoS Pathog 7(6): 2011.
3. Nakamoto, Y., et al., Immune pathogenesis of hepatocellular carcinoma. J Exp Med, 1998. 188(2): p. 341-50.
4. De Palma, M., et al., Tumor-targeted interferon-alpha delivery by Tie2-expressing
monocytes inhibits tumor growth and metastasis. Cancer Cell, 2008. 14(4): p. 299-311.