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.
1987: Degree in Biology, University of Torino, Italy. 1993: Ph.D. in Human Genetics, University of Torino, Italy.
1984-87: undergraduate student in the laboratory of Medical Genetics, Department of Genetics, Biology and Clinical Chemistry, University of Torino, Italy.
1987-88: Post-doctoral fellow in the laboratory of Medical Genetics, Department of Genetics, Biology and Clinical Chemistry, University of Torino; she was awarded with a fellowship from the Associazione Italiana per la Ricerca sul Cancro-AIRC, Italy
From 1988 to 1991 Post-doctoral fellow at the Basel Institute for Immunology, Basel, Switzerland; where she was awarded with a Short Term EMBO Fellowship.
1992-present: Research Assistant, Joint-head with Paolo Dellabona of the Experimental Immunology Unit, DIBIT, San Raffaele Scientific Institute, Milano, Italy.
1998-2009 Holds a position of project leader in the Cancer Immunotherapy and Gene Therapy Program, San Raffaele Scientific Institute, Milano, Italy.
2009-2014 Principal Investigator of the Cancer Immunology and Bio-Immuno therapy Program. San Raffaele Scientific Institute, Milano, Italy.
1. Investigating the development and function of T cells that recognize lipid antigens presented by CD1 molecules. 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 infectious pathogen-derived or cell-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 distinct microRNA signature . We are investigating the miRNA-mRNA network controlling the differentiation program of iNKT cells by integrating gene expression analysis, bioinformatics and specific miRNA or mRNA knockdown experiments. Furthermore, we are obtaining clear evidence both in man and mouse that the presence of iNKT cells plays a protective role against solid or hematologic tumors. We have data demonstrating that iNKT cells control pro-tumor macrophages infiltrating the prostate cancer developing in the TRAMP transgenic mouse model. We are now dissecting the mechanisms by which iNKT cells control the tumor microenvironment. Furthermore, we have established a clear prognostic and functional role for the iNKT/CD1d axis in CLL, both in patients and in the TCL1 mouse transgenic model that develops spontaneous B cell leukemia.
Second, we are interested also in T cells that recognise endogenous lipid antigens presented by CD1a, b, and c molecules, which are not expressed in mice. We have formed the hypothesis that lipids synthesised by malignant cells may stimulate this CD1-restricted T cell response. We have demonstrated that primary AML and B-ALL blasts express CD1c. We have characterized a new lipid antigen that is enriched in acute leukemia and is recognized by CD1c-restricted T cells with anti-leukemia activity. These T cells kill primary leukemia blasts in vitro and control leukemia growth in grafted immunodeficient mice. These findings provide a novel conceptual framework for the development of new forms of immunotherapy of acute leukemia that exploit the effector functions of CD1-restricted T cells specific for self-lipids.
In particular we expect to deliver an adoptive immunotherapy strategy using CD1c self-reactive T cells or TCR-engineered T lymphocytes to treat leukemia.
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. Random mutagenesis throughout the genome characterizes neoplastic transformation and generates many tumor-specific proteins bearing aminoacid substitutions, therefore forming potential unique neo-antigens for the host’s immune system.
To identify somatically mutated genes expressed by colorectal cancer (CRC) and CRC cancer stem cells (CSC), we have implemented an integrated platform based on next generation sequencing coupled to reverse immunology, by which we are characterizing the CD4+ and CD8+ T cell responses against the mutated peptides in each CRC patient from which the tumor has been obtained.
Such a strategy allows to identify strongly immunogenic unique TAAs that can be used to produce individual patient-tailored vaccines whose efficacy can then be tested in well designed clinical trials.
- Lepore M, de Lalla C, Mori L, Dellabona P*, De Libero G*, Casorati G*. Targeting leukemia by CD1c-restricted T cells specific for a novel lipid antigen. Oncoimmunology. 2014 Dec 3;4(3):
- Lepore M, de Lalla C, Ramanjaneyulu GS, Gsellinger H, Consonni M, Garavaglia C, Sansano S, Piccolo F, Scelfo A, Häussinger D, Montagna D, Locatelli F, Bonini C, Bondanza A, Forcina A, Li Z, Ni G, Ciceri F, Jenö P, Xia C, Mori L*, Dellabona P*, Casorati G*, De Libero G*. A novel self-lipid antigen targets human T cells against CD1c+ leukaemias. J. Exp. Med. 211:1363-1377 (2014).
- Trajanoski Z, Maccalli C, Mennonna D, Casorati G, Parmiani G, Dellabona P. Somatically mutated tumor antigens in the quest for a more efficacious patient-oriented immunotherapy of cancer. Cancer Immunol Immunother. 2014 Aug 28.
- Dellabona P, Abrignani S, Casorati G. iNKT cell help to B cells: a cooperative job between innate and adaptive immune responses. Eur J Immunol. 2014 Apr 29.
- de Candia P, Torri A, Gorletta T, Fedeli M, Bulgheroni E, Cheroni C, Marabita F, Crosti M, Moro M, Pariani E, Romanò L, Esposito S, Mosca F, Rossetti G, Rossi RL, Geginat J, Casorati G, Dellabona P, Pagani M, Abrignani S. Intracellular modulation, extracellular disposal and serum increase of MiR-150 mark lymphocyte activation. PLoS One. 2013 Sep 26;8(9):e75348
- Napolitano A, Pittoni P, Beaudoin L, Lehuen A, Voehringer D, MacDonald HR, Dellabona P*, Casorati G*. Functional education of invariant NKT cells by dendritic cell tuning of SHP-1. J Immunol. 2013 Apr 1;190(7):3299.
Highlighted in J Immunol 2012 190.
- Casorati G, de Lalla C, Dellabona P. Invariant natural killer T cells reconstitution and the control of leukemia relapse in pediatric haploidentical hematopoietic stem cell transplantation. Oncoimmunology. 2012 May 1;1(3):355.
- Provasi E, Genovese P, Lombardo A, Magnani Z, Liu PQ, Reik A, Chu V, Paschon DE, Zhang L, Kuball J, Camisa B, Bondanza A, Casorati G, Ponzoni M, Ciceri F, Bordignon C, Greenberg PD, Holmes MC, Gregory PD, Naldini L, Bonini C. Editing T cell specificity towards leukemia by zinc finger nucleases and lentiviral gene transfer. Nat Med. 2012 May;18(5):807.
- Tonti E, Fedeli M, Napolitano A, Iannacone M, von Andrian UH, Guidotti LG, Abrignani S, Casorati G*, Dellabona P*. Follicular helper NKT cells induce limited B cell responses and germinal center formation in the absence of CD4(+) T cell help. J Immunol. 2012. 188(7):3217.
Highlighted in Nat Rev Immunol 2013 13:412-26, and of outstanding interest in Current Opinion in Immunology 2014, 28:12–17
- 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. 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. 41(3):602.
Highlighted for outstanding interest in Current Opinion in Immunology 2014, 26:1–6
- 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. 2011. 140(2):152. Review.
- Canderan G, Gruarin P, Montagna D, Fontana R, Campi G, 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. 5(8):e12014. Erratum in: PLoS One. 2011. 6(1).
- 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. 40(6):1603.
- 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.
- 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. 183(4):2506.
- 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. 113(2):370.
- 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. 2008. 73(11):1010.
- 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. 180(7):4415.
- Galli G, Pittoni P, Tonti E, Malzone C, Uematsu Y, Tortoli M, Maione D, Volpini G, Finco O, Nuti S, Tavarini S, Dellabona P, Rappuoli R, Casorati G*, Abrignani S*. Invariant NKT cells sustain specific B cell responses and memory. Proc Natl Acad Sci USA. 2007. 104(10):3984.
* equal contribution/last author