Giulia Casorati
Giulia Casorati
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
1987: Degree in Biological Science with "summa cum laude", University of Torino, Italy.
1992: Ph.D in Human Genetics from the University of Torino, Italy.

Positions and Employment
1987-1988 Fellow, lab of Medical Genetics, Department of Genetics, Biology and Clinical Chemistry,
University of Torino, Italy.
1988-91: Fellow at the Basel Institute for Immunology, Basel, Switzerland. in Dr. Klaus Karjalainen laboratory.
1992-present: Research Assistent, Joint-head with Paolo Dellabona of the Experimental Immunology Unit, DIBIT, San Raffaele Scientific Institute, Milano, Italy.

Other Experience and Professional Memberships
Member of the Italian Society of immunology and clinical Immunology and allergology SIICA
Member of the Network Italiano per la Bioterapia dei Tumori NIBIT

1987: Awarded a fellowship from the Fondazione Anna Villa Rusconi, Italy
1987: Awarded a fellowship from the Associazione Italiana per la Ricerca sul Cancro (AIRC), Italy
1988: Awarded a Short Term Embo Fellowship

Research activities

Tumor cells express antigens that make them visible to the immune system. Nevertheless tumors escape the immune surveillance and grow by triggering mechanisms that promote immune tolerance. Cancer immunotherapy tries to reestablish the immune surveillance and counteract immune tolerance mechanisms to achieve clinical responses. In our laboratory, we are investigating mechanisms by which innate and adaptive effector T lymphocytes are recruited in the tumor immunesurveillance and strategies to harness their functions for the design of more efficacious immunotherapy protocols.
1. Investigating the development and function of T cells that recognize lipid antigens presented by CD1 molecule There exists a subset of T lymphocytes that recognize lipid antigens presented by CD1 molecules. CD1 isotypes (CD1a, b, c, d) are expressed by APCs and survey different endocytic pathways, where they bind specific sets of exogenous (pathogenderived) or endogenous lipids. The cellular and molecular pathways controlling the development of CD1-restricted T cells are partially known. Furthermore, it is not yet clear what is their role and relevance in the immune response.
We are studying two types of CD1-restricted T cells. First, the invariant (i)NKT cells, which are a distinct lineage of T lymphocytes with innate effector functions, whose development relies on a unique genetic program. We have shown that this program includes a specific profile of microRNAs. We are now investigating the miRNA network controlling the differentiation program of iNKT cells by integrating transcriptomics, bioinformatics and specific miRNA or mRNA knock down experiments. Furthermore, we have hypothesized that iNKT cells may have an adjuvant-like role in the immune response, which is displayed via stimulating the innate immune system to activate adaptive immune responses. We have indeed shown that iNKT cells sustain antibody response to vaccine models and we are presently investigating the mechanisms and topography of their interactions with DCs, B cell and hepatic stellate cells by cell-specific labelling and intravital microscopy. Finally, we are obtaining clear evidence both in man and mouse that the presence of iNKT cells plays a protective role against cancer, both leukemia and adenocarcinoma. Second, we are interested also in T cells that recognise endogenous lipid antigens presented by CD1a, b, and c. We have formed the hypothesis that lipids synthesised by malignant cells may stimulate this CD1-restricted T cell response. We have indeed identified endogenous lipid species that stimulate CD1-restricted self-reactive T cells. By using a variety of approaches, including humanized xenografted immuno-deficient mouse models, we are testing the potential role in the anti-leukaemia response of the second group of CD1-restricted T cells.
2. Discovery of unique tumor antigens and characterization of the specific T cell responses. There is strong evidence that it is possible to induce strong and specific anti-tumor immune responses by using tumor antigens that result from non-synonymous, random mutations in cancer cell genes. We want to test the hypothesis that somatic mutations in 40 selected colon
cancer genes (CAN-genes) generate strongly immunogenic antigens and specific immune responses in patients. The mutations in these CAN-genes are identified by massive parallel sequencing from CRC specimens, followed by a reverse immunology approach that utilizes the mutated peptides to investigated the T cell responses specific for the unique tumor antigens.
Schumann J, Mycko MP, Dellabona P, Casorati G, Macdonald HR. Cutting Edge: Influence of the TCR Vbeta Domain on the Selection of Semi-Invariant NKT Cells by Endogenous Ligands. J Immunol. 2006 Feb 15;176(4):2064-8.

Tassi E, Facchinetti V, Seresini S, Borri A, Dell'antonio G, Garavaglia C, Casorati G, Protti MP.Peptidome from renal cell carcinoma contains antigens recognized by CD4+ T cells and shared among tumors of different histology. Clin Cancer Res. 2006 Aug 15;12(16):4949-57.

Montagna D, Maccario R, Locatelli F, Montini E, Pagani S, Bonetti F, Daudt L, Turin I, Lisini D, Garavaglia C, Dellabona P, Casorati G..Emergence of anti-tumor cytolytic T cells is associated with maintenance of hematological remission in children with acute myeloid leukemia. Blood. 2006 ;108(12):3843-50;

Galli G., P. Pittoni, E. Tonti, C. Malzone, Y. Uematsu, M. Tortoli, D. Maione, G. Volpini, O. Finco, S. Nuti, S. Tavarini1, P. Dellabona, R. Rappuoli, G. Casorati* and S. Abrignani. Invariant NKT cells sustain specific B cell responses and memory Proc. Natl. Acad. Sci. USA. 2007 Mar 6;104(10):3984-9.

Thedrez A, de Lalla C, Allain S, Zaccagnino L, Sidobre S, Garavaglia C, Borsellino G, Dellabona P, Bonneville M, Scotet E, Casorati G. CD4 engagement by CD1d potentiates activation of CD4+ invariant NKT cells. Blood. 2007. 110: 251-8.

Marturano J, Longhi R, Casorati G, Protti MP. MAGE-A3(161-175 )contains an HLA-DRbeta4 restricted natural epitope poorly formed through indirect presentation by dendritic cells. Cancer Immunol Immunother. 2008 Feb;57(2):207-15

Denkberg G, Stronge VS, Zahavi E, Pittoni P, Oren R, Shepherd D, Salio M, McCarthy C, Illarionov PA, van der Merwe A, Besra GS, Dellabona P, Casorati G, Cerundolo V, Reiter Y. Phage display-derived recombinant antibodies with TCR-like specificity against alpha-galactosylceramide and its analogues in complex with human CD1d molecules. Eur J Immunol. 2008 38:829-40.

de Lalla C, Festuccia N, Albrecht I, Chang HD, Andolfi G, Benninghoff U, Bombelli F, Borsellino G, Aiuti A, Radbruch A, Dellabona P, Casorati G. Innate-like effector differentiation of human invariant NKT cells driven by IL-7.
J Immunol. 2008 Apr 1;180(7):4415-24.

Panattoni M, Sanvito F, Basso V, Doglioni C, Casorati G, Montini E, Bender JR, Mondino A, Pardi R. Targeted inactivation of the COP9 signalosome impairs multiple stages of T cell development. J Exp Med. 2008 Feb 18;205(2):465-77.

Cecconi V, Moro M, Del Mare S, Dellabona P, Casorati G. Use of MHC class II tetramers to investigate CD4+ T cell responses: problems and solutions. Cytometry A. 2008 Nov;73(11):1010-8.

Tonti E, Galli G, Malzone C, Abrignani S, Casorati G, Dellabona P. NKT-cell help to B lymphocytes can occur independently of cognate interaction. Blood. 2009 Jan 8;113(2):370-6.

Fedeli M, Napolitano A, Wong MP, Marcais A, de Lalla C, Colucci F, Merkenschlager M, Dellabona P, Casorati G. Dicer-dependent microRNA pathway controls invariant NKT cell development. J Immunol. 2009 Aug 15;183(4):2506-12. Epub 2009 Jul 22.

Li X, Shiratsuchi T, Chen G, Dellabona P, Casorati G, Franck RW, Tsuji M.
Invariant TCR rather than CD1d shapes the preferential activities of C-glycoside analogues against human versus murine invariant NKT cells. J Immunol. 2009 Oct 1;183(7):4415-21. Epub 2009 Sep 4.

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

Cecconi V, Moro M, Del Mare S, Sidney J, Bachi A, Longhi R, Sette A, Protti MP, Dellabona P, Casorati G. The CD4+ T-cell epitope-binding register is a critical parameter when generating functional HLA-DR tetramers with promiscuous peptides. Eur J Immunol. 2010 Jun;40(6):1603-16.

Canderan G, Gruarin P, Montagna D, Fontana R, Melloni G, Traversari C, Dellabona P, Casorati G. An efficient strategy to induce and maintain in vitro human T cells specific for autologous non-small cell lung carcinoma. PLoS One. 2010 Aug 9;5(8):e12014.

Dellabona P, Casorati G, de Lalla C, Montagna D, Locatelli F. On the use of donor-derived iNKT cells for adoptive immunotherapy to prevent leukemia recurrence in pediatric recipients of HLA haploidentical HSCT for hematological malignancies.
Clin Immunol. 2010 Dec 23

de Lalla C, Rinaldi A, Montagna D, Azzimonti L, Bernardo ME, Sangalli LM, Paganoni AM, Maccario R, Di Cesare-Merlone A, Zecca M, Locatelli F, Dellabona P, Casorati G.
Invariant NKT cell reconstitution in pediatric leukemia patients given HLA-haploidentical stem cell transplantation defines distinct CD4+ and CD4- subset dynamics and correlates with remission state. J Immunol. 2011 Apr 1;186(7):4490-9.

de Lalla C, Lepore M, Piccolo FM, Rinaldi A, Scelfo A, Garavaglia C, Mori L, De Libero G, Dellabona P, Casorati G. High-frequency and adaptive-like dynamics of human CD1 self-reactive T cells. Eur J Immunol. 2011 Mar;41(3):602-10.
Project Title:
Development and function of unconventional T lymphocytes specific for lipid antigens.
A significant proportion of human T lymphocytes recognize lipid antigens presented by the MHC class I-like molecules CD1, which are divided in three groups: group 1, comprise CD1a, CD1b and CD1c; group 2 and 3, contain CD1d and CD1e, respectively. T lymphocytes can recognize group 1 CD1 expressing cells in the absence of foreign antigens, implying that these molecules are loaded with self-lipid antigens. These CD1 self-reactive T cells are surprisingly frequent in men (de Lalla et al. EJI. 41. 2011), suggesting that they might play an important role in the immune response. Recently, we have identified a potential role of group 1 CD1 self-reactive T cells in leukemia immunesurvailance (Lepore and de Lalla, in preparation). The absence of this lymphocytes population in mice, which express only CD1d molecules, has prevented so far the use of informative mouse models to investigate their development. To overcome these limitations, we have generated a humanized mouse transgenic model in which the human CD1c gene is expressed in thymocytes and professional APCs (monocytes, DCs and B cells), replicating the human CD1c expression pattern. Taking advantage of these tg mice, the project will mechanistically address the following questions:
1) The cellular and molecular mechanisms underlying the development and selection of CD1c-restricted T cells;
2) The role of CD1c-restricted T cells in the immune response against exogenous antigens and how they interplay with conventional T, monocytes, DCs and B cells in vivo;
3) The role of CD1c-restricted T cells in tumor control.
The data obtained with the CD1c Tg mice, verified when possible with data obtained from human subjects, will help gaining a deeper understanding of the physiology of this abundant yet mysterious T cell immune response.

Project Title:
Immunosurveilance of leukemia by a novel subset of T lymphocytes specific for self-lipid antigens presented by CD1 molecules.
One major interests of our research group is the study of T lymphocytes that recognize lipid antigens presented by CD1 molecules. In human CD1 molecules are divided in three groups: group 1 comprises CD1a, CD1b and CD1c, while group 2 and 3 contain CD1d and CD1e, respectively. Differently from classic MHC, CD1 molecules are not polymorphic and present antigens of lipid origin instead of peptides.
Some T lymphocytes can recognize cells expressing group 1 CD1 molecules in the absence of deliberately added foreign antigens, implying that CD1 molecules are loaded with self-lipid antigens.
We hypothesize that this �self-reactive� T cell response might play a role in cancer immunesurveillance, where self-antigens are targets of immune responses. We have obtained data showing that the frequency of self-reactive CD1-restricted T cells in men is surprisingly high, suggesting that they might represent an important arm of the immune response (de Lalla C. et al. EJI 2011). We have also recently found that a high percentage of leukemia cells from patients express CD1 group 1 molecules and are recognized by CD1 specific T cell clones. Finally, we have identified a lipid antigen isolated from leukemia cell lines that activate self-reactive CD1c-restricted T cells (Lepore and de Lalla, in preparation).
In the light of the above considerations, this project aims at understanding the role of this novel T cell population in leukemia immunesurveillance. The project will integrate different experimental approaches: i cellular and molecular characterization of the CD1-restricted T cell responses in leukemia patients, using state of art reagents for single cell analysis; ii an in vivo model of human leukemia xenotransplant in immunodeficient mice adoptively transferred with anti leukemia CD1 restricted T cell clones or polyclonal T cells engineered with lentiviral vectors coding for the anti CD1c TCR chains; iii identify the recently characterized lipid antigen recognized by CD1c specific T cell clones on freshly isolated blasts.