Anna Mondino
Anna Mondino
e-mail:
affiliation: San Raffaele Scientific Institute
research area(s): Immunity And Infection, Cancer Biology
Course: Basic and Applied Immunology
University/Istitution: Università Vita-Salute San Raffaele
Name: Anna Mondino
Date of birth:September 1, 1965, Turin, Italy
Citizenship: Italian
Marital Status:Married, Two children

Address: Division of Immunology, Transplantation and Infectious Diseases
San Raffaele Scientific Institute
Via Olgettina, 58, 20132 Milan, Italy
Telephone: 39-02-2643-4801
Fax: 39-02-2643-4844
E-mail: anna. mondino@hsr.it


Education:

1988 Master in Biological Sciences (Summa cum Laude, 110/110),
University of Turin, Italy
1992 Ph.D., Molecular Oncology
University of Turin, Italy.
1993-Feb. 1998 Postdoctoral Training
University of Minnesota, Medical School, Minneapolis, MN, USA

Professional experience:

1986-1988 Undergraduate student
Department of Biomedical Science and Oncology, Turin, Italy
1988-1989 Research Fellow
Department of Biomedical Science and Oncology, Turin, Italy
1989-1992 Ph.D. student in Molecular Oncology
1989-1991: Department of Biomedical Science and Oncology, Turin, Italy
1991-1992: Department of Pharmacology, New York University, New York, USA
1993-Feb. 1998 Postdoctoral Associate
Department of Microbiology
University of Minnesota, Medical School
Minneapolis, MN, USA
April 1998-1999 Research Associate
Department of Molecular Biology and Functional Genomic
San Raffaele Scientific Institute, DIBIT, Milan, Italy
Since January 2000 Head of Lymphocyte Activation Unit
Division of Immunology, Transplantation and Infectious Diseases
Program in Immunology, Bio-Immuno-gene therapy of Cancer
San Raffaele Scientific Institute, DIBIT, Milan, Italy

Professional Activities:

1999-2002 Member, Committee of institutional seminar program
1998-2010 Organizer, Immunology Journal Club
2003-2010 Member, Office of Graduate School, PhD Program in cellular and Molecular Biology Open University and Vita-Salute San Raffaele University
2004-2010 Member of Molecular Medicine PhD Program (Immunology section).
2009-2010 Organizer of the San Raffaele Scientific Retreat
2010-Date Member of the International Postdoctoral Programme.
2010-Date Member of the Institutional Appointment and Promotion Committee
2010-Date Member of the Division of Immunology Stretagic committee
2004-Date Invited Reviewer: Proceedings of the National Academy of Sciences USA, Journal of Immunology, Cancer Research, Blood, Human gene Therapy, Stem Cell, Immunology letters, Plos One, Cancer Research Foundation UK, Science Foundation Ireland, Austrian Science Fund (FWF)
The research activity of my group is currently focused on gaining a deeper understanding of the cellular and molecular mechanisms at the basis of adaptive immunity, with emphasis on the role of T lymphocytes in immunological memory and/or tolerance to tumors. We have developed tools allowing the tracing of individual tumor-specific T cell in mouse models of human diseases. Most recently we have developed a new strategy allowing the cure of advanced prostate cancer. We are actively collaborating with clinicians for the clinical translation of the protocol. We have also defined a new mouse model allowing studying the immune competence of patients with tuberous sclerosis complex.
Colombetti S., V. Basso, D.L. Mueller and A. Mondino. Prolonged TCR/CD28 engagement drives IL-2 independent T cell clonal expansion through signaling mediated by the mammalian Target of Rapamycin (mTOR). J Immunol. 2006 176(5):2730-8.

Mondino A. and D.L. Mueller. mTOR at the crossroads of T cell proliferation and tolerance. Semin Immunol. 2007 (3):162-72.

Zimmermann V.S., A. Casati, C. Schiering, S. Caserta, R. Hess Michelini, V. Basso and A. Mondino. Tumors hamper the immunogenic competence of CD4+ T cell-directed dendritic cell vaccination. J Immunol. 2007 179:2899-909.

Bellone M., * Mondino A*. and Corti A. * Vascular targeting, chemotherapy and active immunotherapy: teaming up to attack cancer. Trends in Immunol. 2008; 29(5):235-41. (* equal contribution)

Caserta S., P. Alessi, J. Guarnerio, V. Basso and A. Mondino. Synthetic CD4+ T cell targeted antigen presenting cells elicit protective anti-tumor responses. Cancer Res. 2008 15;68(8):3010-8.

Kaneko S., Mastaglio S., Bondanza A., Punzoni M., Sanvito F., Aldrighetti L., Radrizzani M., La Seta-Catamancio S., Provasi E., Mondino A., Nagasawa T., Fleischhauer K., Russo V., Traversari C., Ciceri F., Bordignon C., and C. Bonini. IL-7 and IL-15 allow the generation of suicide gene-modified alloreactive self-renewing central memory human T lymphocyte. Blood. Blood. 2009: 113(5):1006-15.

Caserta S, Alessi P, Basso V, Mondino A. IL-7 is superior to IL-2 for ex vivo expansion of tumour-specific CD4(+) T cells. Eur J Immunol. 2010 Feb;40(2):470-9.

Mondino A, Dardalhon V, Michelini RH, Loisel-Meyer S, Taylor N. Redirecting the immune response: Role of adoptive T cell therapy Hum Gene Ther. 2010 May;21(5):533-41.Mar 4. [Epub ahead of print]

Pouw N., Treffers-Westerlaken E., Mondino A., Lamers C., and R. Debets. TCR gene-engineered T cells: limited T cell activation and combined use of IL-15 and IL-21 to ensure minimal differentiation and maximal antigen-specificity. Mol. Immunol. 2010 Apr;47(7-8):1411-20

Hess Michelini R., Freschi M., Manzo T., Jachetti E., Degl’Innocenti E., Grioni M., Basso M., Bonini C., Simpson E., Mondino A.* and M. Bellone*. (* co-last) Concomitant tumor and minor histocompatibility antigen-specific immunity initiate rejection and maintain remission from established spontaneous solid tumors. Cancer Res. 2010 May 1;70(9):3505-14. Epub 2010 Apr 13.

Schiering C, Guarnerio J, Basso V, Muzio L, Mondino A. Antigen-experienced CD4(+) T cells limit naïve T-cell priming in response to therapeutic vaccination in vivo. Cancer Res. 2010 Aug 1;70(15):6161-70. Epub 2010 Jul 14

Caserta S., Kleczkowska J, Mondino A. and Rose Zamoyska. Reduced functional avidity promotes central and effector memory CD4 T cell responses to tumor-associated antigens. J. Immunol. 2010 Dec 1;185(11):6545-54.

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

Tomasoni R. and A. Mondino. The Tuberous Sclerosis Complex: balancing proliferation and survival. Biochemical Society Transactions. 2011 Apr 1;39(2):466-71.

Basso V., Corbetta S., Gualdoni S., Tonoli D., Poliani P.L., Sanvito F., Doglioni C., Mondino A. and I. Curtis2* (*co-last). Absence of Rac1 and Rac3 GTPases in the nervous system hinders thymic, splenic and immune-competence development. Eur. J. Immunol. 2011. May;41(5):1410-9. doi: 10.1002/eji.201040892. Epub 2011 Apr 15.

Tomasoni R., Basso V., Pilipow K., Sitia G., Saccani S., Agresti A., Mietton F., Natoli G., Colombetti S. *, and A.Mondino,* (*co-last).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.

Tomasoni R., Negrini S., Fiordaliso S. Klajn A., Tkatch T., Mondino *, Meldolesi J.*and R. D’Alessandro. (*correspondent authors). REST, TSC2 and [beta]-catenin, interconnected in a signaling loop, govern proliferation and functions of PC12 neural cells. J. Cell Sci. In press.
Project Title:
Attacking tumors with TCR-redirected T cells
Central and peripheral mechanisms of tolerance hinder protective immunity against tumor. We have recently found that non myeloablative allogeneic transplantation and tumor-specific vaccination overcomes tumor-specific tolerance allowing acute rejection of spontaneous prostate cancer and prolonging disease-free survival (Hess Michelini, Cancer Res. 2010; Manzo et al. J. Immunol. 2011; Manzo et al. 2011, Submitted). Theraperutic efficacy relied on the synergy of tumor and minor histocompatibility antigen-specific T cells. To avoid possible graft versus host disease, the major limitation of allogeneic transplantation, we are adopting a TCR transfer strategy based on the possibility to reconstruct minimal lymphocyte combinations, capable of rejecting the tumor, but unable to cause overt host tissue recognition. We are currently transducing autologous T cells with a high affinity tumor-specific antigen, and a Y-encoded minor histocompatibility antigen. Aim of the student will be to define homing, survival and functional abilities of transduced T cells upon in vivo infusion. Suicide genes will be employed to control T cell persistence. Short-term effector functions and long term persistence of the cells will be monitored by flow cytometry, immunohistochemestry and confocal analysis. Furthermore, as we have found that the potency of adoptive immunotherapy with TCR-transduced T cells is hindered by pre-existing memory lymphocytes (Schiering, Guarnerio, Cancer Res. 2010 and Basso, unpublished), the student will also characterize the interplay of endogenous naïve/memory cells with adoptively transferred TCR transgenic or TCR redirected T cells. Results generated by this research activity will be instrumental to better define the molecular mechanism of T cell tolerance and tumor rejection and to future clinical translation.

References
1. Hess Michelini R., Freschi M., Manzo T., Jachetti E., Degl’Innocenti E., Grioni M., Basso M., Bonini C., Simpson E., Mondino A.* and M. Bellone*. (* co-last)
Concomitant tumor and minor histocompatibility antigen-specific immunity initiate rejection and maintain remission from established spontaneous solid tumors. Cancer Res. 2010 May 1;70(9):3505-14. Epub 2010 Apr 13.
2. Schiering C, Guarnerio J, Basso V, Muzio L, Mondino A. Antigen-experienced CD4(+) T cells limit naïve T-cell priming in response to therapeutic vaccination in vivo. Cancer Res. 2010 Aug 1;70(15):6161-70. Epub 2010 Jul 14
3. Manzo T, Hess Michelini R., Basso V., Ricupito A., Chai J-C., Simpson E., Bellone M. * and A. Mondino*. (* co-last). Concurrent allo-recognition has a limited impact on post-transplant . J. Immunol. 2011 Feb 1;186(3):1361-8.
4. Manzo T, Hess Michelini R., Freschi, M., Basso V., Bonini C., Simpson E., Bellone M. * and A. Mondino*. (* co-last). Multiple minor histocompatibility antigens mismatched hematopoietic cell transplantation cures mice of autochthonous prostate adenocarcinoma. 2011. Submitted.
5. Hess Michelini R., Manzo T., Freschi M., Basso M., Rocchi M., M. Bellone* and A. Mondino. Tumor-specific vaccination is critical for prostate cancer infiltration and eradication following allogeneic transplantion. 2011. In Preparation.


Project Title:
Characterizing the role of the tuberous sclerosis complex and mTOR in cell fate determination.
The Ser/Thr mammalian target of rapamycin (mTOR) kinase orchestrates metabolisms, growth, proliferation and survival of a variety of primary and transformed cells. We have studied the role of mTOR in T cell biology and found it to be critical for the maintenance of antigen responsiveness (Colombetti, J Immunol 2002), but dispensable for IL-2-driven cell proliferation (Colombetti, J Immunol 2006). More recently, we found that both mTOR complex 1 (mTORC1) and mTORC2 are controlled by TCR engaging ligands and control DNA methylation of Ifng, Il4 and FoxP3, and the ability to acquire effector and regulatory functions (Tomasoni, E. J. Immunol 2011). These data unveil a previously unrecognized role for mTOR in inducing epigenetic modification of genes important for cell fate determination. Furthermore, by T-lineage-restricted inactivation of TSC1, we defined its critical role in controlling mTORC1 and mTORC2 activation during thymic development and lymphocyte homeostasis. Aim of the PhD project will be to: 1) Define mTOR-dependent signaling linked to epigenetic gene control. 2) Identify TSC/mTOR dependent epigenetic signatures and 3) validate the newly defined mTOR-targets/signatures in in vivo model of antigen-driven responses and tumor development. To these aims the student will undertake gene expression profiling analysis and validate identified targets by gene expression/function studies, Chip-on-chip analysis, and RNAi-based strategies in vitro in primary T cells and in transformed cells and in vivo in animal models of antigen-driven T cell responses, allotransplantation and tumor disease.

References
1. Colombetti S., Benigni F., Basso V., and A. Mondino. Clonal anergy is maintained independently of T cell proliferation. J. Immunol. 169: 6178-86. 2002.
2. Colombetti S., V. Basso, D.L. Mueller and A. Mondino. Prolonged TCR/CD28 engagement drives IL-2 independent T cell clonal expansion through signaling mediated by the mammalian Target of Rapamycin (mTOR). J Immunol. 2006 176(5):2730-8.
3. Mondino A. and D.L. Mueller. mTOR at the crossroads of T cell proliferation and tolerance. Semin Immunol. 2007 (3):162-72.
4. Tomasoni R., Basso V., Pilipow K., Sitia G., Saccani S., Agresti A., Mietton F., Natoli G., Colombetti S. *, and A.Mondino,* (*co-last).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.
5. Tomasoni R., Negrini S., Fiordaliso S. Klajn A., Tkatch T., Mondino *, Meldolesi J.*and R. D’Alessandro. (*correspondent authors). REST, TSC2 and [beta]-catenin, interconnected in a signaling loop, govern proliferation and functions of PC12 neural cells. J. Cell Sci. In press.