Matteo Bellone
Matteo Bellone
affiliation: San Raffaele Scientific Institute
research area(s): Cancer Biology, Immunity And Infection
Course: Basic and Applied Immunology
University/Istitution: Università Vita-Salute San Raffaele
1986 School of Medicine, Universita' degli Studi, Milano; MD (summa cum laude)
1986 College of Physicians and Surgeons, Member
1989 National Board of Allergology and Clinical Immunology, Universita' degli Studi, Milano; Specialist (summa cum laude)
1988-1991 University of Minnesota, Saint Paul, MN-USA; Postdoctoral fellow; immunopathology
1991-1992 Istituto Scientifico San Raffaele, Milano; Postdoctoral fellow; Immunology of cancer
Professional experiences
1986 resident Department of Internal Medicine, University of Milan School of Medicine
1987 Assistant, leutenant Clinical Laboratory, Ospedale Militare di Milan, Milano
1988-1991 Post-doctoral fellow Department of Biochemistry, University of Minnesota, St Paul, MN-USA
1991-1992 Post-doctoral fellow Department of Internal Medicine, University of Milan School of Medicine
1992-2002 Investigator Istituto Scientifico San Raffaele, Milan
1994-1999 Cultore della Materia Department of Internal Medicine, University of Milan School of Medicine
1999-to date Professore a Contratto Vita-Salute University School of Medicine, Milan
2002-2003 Senior Investigator Istituto Scientifico San Raffaele, Milan
2004-to date Head Unit of Cellular Immunology, Istituto Scientifico San Raffaele, Milan
Major goal of our research is to achieve a deeper understanding of the molecular events regulating the interactions among transformed cells, their surrounding stroma and the immune system during the different phases of tumor development and progression. This knowledge is then implemented to identify means whereby induce in vivo a therapeutic tumor-specific immune response. Final goal is to translate the most promising among these novel therapies into clinical trials.

The transgenic adenocarcinoma of the mouse prostate (TRAMP) model, a primary model of prostate cancer (PC), is implemented to thoroughly characterize the interactions between tumor-specific T lymphocytes and spontaneous PC. We are investigating several immunoescape mechanisms adopted by tumor initiating and more differentiated cells, and we have already attempted several strategies to overcome them. We are also designing novel therapeutic approaches that combine more conventional therapies with immunotherapy. A more detailed description of the main projects follows.

Dynamic interactions between PC and the immune system. In TRAMP mice, as it frequently occurs in PC patients, tumor development and progression associates with the induction of a progressive state of profound and selective immune tolerance to PC. So far, none of the best-characterized mechanisms of tumor escape [e.g. regulatory T cells and myeloid derived suppressor cells] although existing in tumor-bearing TRAMP mice, impinges on PC-tolerance. Novel mechanisms are investigated.

Combined therapeutic strategies for cancer. We are investigating the possibility of combining microenvironment-modifying agents with chemotherapy and active or adoptive immunotherapy in the attempt to unravel synergistic therapeutic activities. This approach aims at improving penetration of activated lymphocytes and chemotherapeutic drugs favoring their local anti-tumor and immune adjuvant effects.

Prostate cancer stem/initiating cells as targets of immunosurveillance and active immunotherapy. Goal of this project is to establish whether prostate cancer stem/initiating cells (PCSC) are involved in tumorigenesis, and are antigenic and/or immunogenic. Studies are conducted both in TRAMP mice and humans. Because of the relevant similarities between TRAMP and human PC, it is expected that the results obtained in the mouse model will be rapidly translated to the human pathology.
Rigamonti N, Capuano G, Ricupito A, Jachetti E, Grioni M, Generoso L, Freschi M, Bellone M. Modulators of arginine metabolism do not impact on peripheral T-cell tolerance and disease progression in a model of spontaneous prostate cancer. Clin Cancer Res, 2011 Jan 19. [Epub ahead of print].

Manzo T, Hess Michelini R, Basso V, Ricupito A, Chai J-G, Simpson E, Bellone M and Mondino A. Concurrent allo-recognition has a limited impact on post-transplant vaccination. J Immunol, 2011 Feb 1;186(3):1361-8. Epub 2011 Jan 5

Michelini RH, Freschi M, Manzo T, Jachetti E, Degl"Innocenti E, Grioni M, Basso V, Bonini C, Simpson E, Mondino A and Bellone M. Concomitant tumor and minor histocompatibility antigen-specific immunity initiate rejection and maintain remission from established spontaneous solid tumors. Cancer Res., 2010, May 1;70:3505-14.

Bellone M, Ceccon M, Grioni M, Jachetti E, Calcinotto A, Napolitano A, Freschi M, Casorati G, and Dellabona P. iNKT cells control mouse spontaneous carcinoma independently of tumor-specific cytotoxic T cells. PloS-One, 2010 Jan 13;5(1):e8646.

Capuano G, Rigamonti N, Grioni M, Freschi M, and Bellone M.
Modulators of the arginine metabolism support cancer immunosurveillance.
BMC Immunol, 2009, Jan 9;10(1):1. [Epub ahead of print].

Bertilaccio MTS, Grioni M, Sutherland BW, Degl"Innocenti E, Freschi M, Jachetti E, Greenberg, NM, Corti A, and Bellone M. Vasculature-targeted tumor necrosis factor-alpha increases the therapeutic index of doxorubicin against prostate cancer. Prostate, 2008 Apr 24 [Epub ahead of print].

Degl"Innocenti E, Grioni M, Capuano G, Jachetti E, Freschi M, Bertilaccio MTS, Hess-Michelini R, Doglioni C, and Bellone M. Peripheral T cell tolerance associated with prostate cancer is independent from CD4+CD25+ regulatory T cells. Cancer Res., 2008, 68:292-300.

Bellone M, Mondino A, and Corti A. Vascular targeting, chemotherapy and active immunotherapy: teaming up to attack cancer. Trends Immunol, 2008, 29:235-41.

Boni M, Iezzi G., Degl"Innocenti E, Grioni M, Camporeale A. and Bellone M. Prolonged exposure of dendritic cells to maturation stimuli favor theinduction of type-2 cytotoxic T lymphocytes. Eur. J. Immunol. 2006, 36:3157-3166.

Iezzi G., Boni M, Degl"Innocenti E, Grioni M, Bertilaccio MTS and Bellone M. Type-2 cytotoxic T lymphocytes modulate the activity of dendritic cells towards type-2 immune responses. J. Immunol. 2006, 177: 2131-2137.

Degl"Innocenti E, Grioni M, Boni M, Camporeale A, Bertilaccio S, Freschi M, Monno A, Arcelloni C, Greenberg NM and Bellone M. Peripheral T cell tolerance occurs early during spontaneous prostate cancer development and can be rescued by dendritic cell immunization. Eur J Immunol., 2005, 35(1):66-75.

Bellone M, Camporeale A, Boni A. Dendritic cell activation kinetics and cancer immunotherapy
J Immunol., 2004, 172 (5): 2727-2728.

Camporeale A, Boni A, Iezzi G, Degl"innocenti E, Grioni M, Mondino A, Bellone M. Crirical impact of the kinetics of dendritic cell activation on the in vivo induction of tumor-specific T lymphocytes. Cancer Res., 2003, 63:3688-3694.

Castiglioni P, Martin-Fontecha A, Milan G, Tomajer V, Magni F, Michaelsson J, Rugarli C, Rosato A and Bellone M. Apoptosis-dependent subversion of the T-lymphocyte epitope hierarchy in lymphoma cells. Cancer Res., 2002, 62:1116-1122.

Bellone M, Cantarella D, Ronchetti A, Crosti MC, Castiglioni P, Moro M, Garancini MP, Casorati G and Dellabona P. Relevance of the tumor antigen in the definition of immunotherapeutic strategies for cancer. J. Immunol., 2000, 165:2651-2656.

Bellone M. Apoptosis, cross-priming, and the fate of the antigen specific immune response. Apoptosis, 2000, 5:307-314.
Project Title:
Cross-talk between prostate cancer initiating cells and the immune system
Major goal of the proposed research is to verify if cancer stem-like initiating cells (CSC) can be targeted in vivo by the immune system. This working hypothesis is based on several experimental evidences. Indeed, normal stem cells are endowed with immunosuppressive mechanisms that partially protect them from the attack by the immune system. Few publications suggest that in vitro also CSC possess immunosuppressive activities. Nevertheless, CSC can be killed in vitro by cytotoxic lymphocytes, and can be used in vivo as antigen source for anti-tumor vaccines. In addition, in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model of human prostate cancer, we have evidence that prostate CSC (PCSC) inhibit the in vitro proliferation and full maturation/activation of both dendritic cells (DC) and T lymphocytes, which acquire a modulated phenotype. Hence, aims of this research project will be i) to identify the mechanism by which PCSC inhibit DC and T cells; ii) to define where in vivo PCSC suppress the tumor-specific immune response; and iii), to define whether PCSC can be targeted by antigen-specific immune responses. These aims will be addressed by standard in vitro and in vivo immunological procedures, as well as by high throughput screening at the genetic and protein levels, and will involve a network of research units with multidisciplinary expertise. Results of this research will extend our knowledge of the mechanisms governing tumor/immune system interactions. Because of the similarities between TRAMP and human prostate cancer, our results may also have relevant implications for cancer immunotherapy by disclosing novel potential targets of human T cell responses.

Project Title:
Identification of mechanisms of local immunosuppression in prostate cancer
The pathogenesis of prostate cancer (PC), the third cause of death for neoplasia among men worldwide, has been linked to chronic inflammation. PC may also represent a site of acquired immune privilege, where several mechanisms suppress both locally and systemically the tumor-specific immune response. Aim of the proposed research is to investigate mechanisms of immunosuppression associated with chronic inflammation and prostate cancer. In the transgenic adenocarcinoma of the mouse prostate (TRAMP) model we will phenotypically and functionally characterize the inflammatory microenvironment associated with development and progression of spontaneous prostate cancer. Standard in vitro and in vivo immunological procedures, as well as procedures of high throughput screening at the genetic and protein levels will be implemented to define the mechanisms by which the tumor-specific immune response is suppressed in TRAMP mice. Once identified in the mouse model, similar immunosuppressive mechanisms will be investigated in prostate cancer patients. Finally, we will design novel strategies to overcome the immunosuppressive tumor microenvironment.