San Raffaele Cimena, Italy
San Raffaele Cimena, Italy

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Mazzoleni S.,Neural Stem Cell Biology Unit | Jachetti E.,Gene Therapy and Biolmmunotherapy of Cancer | Jachetti E.,Cellular Immunology Unit | Morosini S.,Neural Stem Cell Biology Unit | And 9 more authors.
Stem Cells Translational Medicine | Year: 2013

The relevant social and economic impact of prostate adenocarcinoma, one of the leading causes of death in men, urges critical improvements in knowledge of the pathogenesis and cure of this disease. These can also be achieved by implementing in vitro and in vivo preclinical models by taking advantage of prostate cancer stem cells (PCSCs). The best-characterized mouse model of prostate cancer is the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. TRAMP mice develop a progressive lesion called prostatic intraepithelial neoplasia that evolves into adenocarcinoma (AD) between 24 and 30 weeks of age. ADs often metastasize to lymph nodes, lung, bones, and kidneys. Eventually, approximately 5% of the mice develop an androgen-independent neuroendocrine adenocarcinoma. Here we report the establishment of long-term self-renewing PCSC lines from the different stages of TRAMP progression by application of the neurosphere assay. Stagespecific prostate cell lines were endowed with the critical features expected from malignant bona fide cancer stem cells, namely, self-renewal, multipotency, and tumorigenicity. Notably, transcriptome analysis of stage-specific PCSCs resulted in the generation of well-defined, meaningful gene signatures, which identify distinct stages of human tumor progression. As such, TRAMP-derived PCSCs represent a novel and valuable preclinical model for elucidating the pathogenetic mechanisms leading to prostate adenocarcinoma and for the identification of molecular mediators to be pursued as therapeutic targets. © AlphaMed Press 2013.


Michelini R.H.,San Raffaele Scientific Institute | Michelini R.H.,Cellular Immunology Unit | Michelini R.H.,University of California at San Diego | Manzo T.,San Raffaele Scientific Institute | And 10 more authors.
Cancer Research | Year: 2013

Vaccination can synergize with transplantation of allogeneic hematopoietic stem cells to cure hematologic malignancies, but the basis for this synergy is not understood to the degree where such approaches could be effective for treating solid tumors. We investigated this issue in a transgenic mouse model of prostate cancer treated by transplantation of a nonmyeloablative MHC-matched, single Y chromosome-encoded, or multiple minor histocompatibility antigen-mismatched hematopoietic cell preparation. Here, we report that tumordirected vaccination after allogeneic hematopoietic stem cell transplantation and donor lymphocyte infusion is essential for acute graft versus tumor responses, tumor regression, and prolonged survival. Vaccination proved essential for generation of CD8+ IFN-g+ tumor-directed effector cells in secondary lymphoid organs and also for IFN-g+ upregulation at the tumor site, which in turn instructed local expression of proinflammatory chemokines and intratumoral recruitment of donor-derived T cells for disease regression. Omitting vaccination, transplanting IFN-g-deficient donor T cells, or depleting alloreactive T cells all compromised intratumoral IFN-g-driven inflammation and lymphocyte infiltration, abolishing antitumor responses and therapeutic efficacy of the combined approach. Our findings argue that posttransplant tumor-directed vaccination is critical to effectively direct donor T cells to the tumor site in cooperation with allogeneic hematopoietic cell transplantation. © 2013 American Association for Cancer Research.


Jachetti E.,Cellular Immunology Unit | Mazzoleni S.,Neural Stem Cell Unit | Grioni M.,Cellular Immunology Unit | Ricupito A.,Cellular Immunology Unit | And 7 more authors.
OncoImmunology | Year: 2013

According to the cancer stem cell (CSC) theory, therapies that do not target the CSC compartment have limited, if any, chances to eradicate established tumors. While cytotoxic T lymphocytes (CTLs) have the potential to recognize and kill single neoplastic cells within a tissue, whether CSC s can be targeted by the immune system during spontaneous or vaccination-elicited responses is poorly defined. Here, we provide experimental evidence showing that CSC lines established from the prostate of transgenic adenocarcinoma of the mouse prostate (TRAMP) mice expressed prostate cancer-associated antigens, MHC Class I and II molecules as well as ligands for natural killer (NK) cell receptors. Indeed, CSC were targets for both NK cell- and CTL-mediated cytotoxicity, both in vitro and in vivo. The administration of dendritic cells pulsed with irradiated CSC s induced a tumor-specific immune response that was more robust than that induced by dendritic cells pulsed with differentiated tumor cells, delayed tumor growth in mice challenged with prostate CSC s and caused tumor regression in TRAMP mice. Thus, CSC are targeted by both innate and adaptive immune responses and might be exploited for the design of novel immunotherapeutic approaches against cancer. © 2013 Landes Bioscience.


Bellone M.,Cellular Immunology Unit | Ceccon M.,Cellular Immunology Unit | Grioni M.,Cellular Immunology Unit | Jachetti E.,Cellular Immunology Unit | And 7 more authors.
PLoS ONE | Year: 2010

Background: CD1d-restricted invariant NKT (iNKT) cells are a subset of T lymphocytes endowed with innate effector functions that aid in the establishment of adaptive T and B cell immune responses. iNKT cells have been shown to play a spontaneous protective role against experimental tumors. Yet, the interplay between iNKT and tumor-specific T cells in cancer immune surveillance/editing has never been addressed. The transgenic adenocarcinoma of the mouse prostate (TRAMP) is a realistic model of spontaneous oncogenesis, in which the tumor-specific cytotoxic T cell (CTL) response undergoes full tolerance upon disease progression. Principal Findings:We report here that lack of iNKT cells in TRAMP mice resulted in the appearance of more precocious and aggressive tumors that significantly reduced animal survival. TRAMP mice bearing or lacking iNKT cells responded similarly to a tumor-specific vaccination and developed tolerance to a tumor-associated antigen at comparable rate. Conclusions: Hence, our data argue for a critical role of iNKT cells in the immune surveillance of carcinoma that is independent of tumor-specific CTL. Copyright: © 2010 Bellone et al.


PubMed | Cellular Immunology Unit
Type: Journal Article | Journal: PloS one | Year: 2010

CD1d-restricted invariant NKT (iNKT) cells are a subset of T lymphocytes endowed with innate effector functions that aid in the establishment of adaptive T and B cell immune responses. iNKT cells have been shown to play a spontaneous protective role against experimental tumors. Yet, the interplay between iNKT and tumor-specific T cells in cancer immune surveillance/editing has never been addressed. The transgenic adenocarcinoma of the mouse prostate (TRAMP) is a realistic model of spontaneous oncogenesis, in which the tumor-specific cytotoxic T cell (CTL) response undergoes full tolerance upon disease progression.We report here that lack of iNKT cells in TRAMP mice resulted in the appearance of more precocious and aggressive tumors that significantly reduced animal survival. TRAMP mice bearing or lacking iNKT cells responded similarly to a tumor-specific vaccination and developed tolerance to a tumor-associated antigen at comparable rate.Hence, our data argue for a critical role of iNKT cells in the immune surveillance of carcinoma that is independent of tumor-specific CTL.

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