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Falisi, Erika (2011) Caratterizzazione di una sottopopolazione mieloide umana analoga ai promielociti e dotata di attività immunosoppressoria. [Tesi di dottorato]

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Abstract (inglese)

The ability of the immune system to avoid self-reactivity and autoimmune diseases is achieved by central and peripheral tolerance. Immune tolerance is susteined by different population, one of which is represented by myeloid-derived suppressor cells (MDSC). MDSC are a heterogeneous population of cells consisting of myeloid progenitor cells and immature myeloid cells that are able to suppress both adaptative and innate immunity. In pathological conditions, such as cancer, various infectious diseases and autoimmune diseases, the release of soluble factors induce the increase of myelopoiesis and a partial block of the maturation of myeloid cells. These soluble factors are also believed to be involved in the mobilization and activation of MDSC. MDSC was found in tumour-bearing mice but also in cancer patients. While the phenotype of murine MDSC is well defined by specific markers, like Gr-1, CD11b e IL4Rα, the immunophenotype of human MDSC is still not well defined. In recent years, both in tumour-bearing mice and in cancer patients, MDSC was identified with granulocytes or monocytes features.
In this work we demonstrated that human MDSC can be induced in vitro by cytokine treatment of myeloid progenitors. Our data show that the combination of G-CSF and GM-CSF induce the accumulation of immature myeloid cells (BM-MDSC) with features resembling those we identified in the blood of cancer patients. We also demonstrated that BM-MDSC are able to suppress T cells proliferation and that this suppression is accompanied by the downregulation of CD3ζ and CD3ε chains and by the reduction of IFN-γ secreted by activated lymphocyte.
Since BM-MDSCs consist of a heterogeneous population, we focused our research to identify the subpopulation of BM-MDSC characterized by the suppressive activity. We demonstrated that human MDSC are immature cells blocked in a particular stage of differentiation. This cells, identifided by the phenotype CD16-/CD11blow/-, showed morphological features of ex-vivo-bone marrow isolated promyelocytes but, unlike these, they are smaller, less grainy, and are able to suppress T lymphocyte proliferation also by CD3ε downregulation. We also observed that the suppressive subpopulation is composed by other two fractions that distinguish each other by a different emission in the red wavelenght, a different grain and a different ability to suppress T lymphocyte proliferation.
In the second section of this work we focused in the evaluation of chemotherapy on the accumulation and the functionality of MDSC, one of the main population involved in tumor immunosuppression and in the failure of immunotherapy. Our data showed that, in analogy to the results obtained in mice, 5-fluorouracil is able to remove the suppressive effect of BM-MDSCs on T lymphocyte proliferation. These observation allow us to suggest the use of chemotherapy like adiuvant in immunotherapy approaches.

Abstract (italiano)

Il sistema immunitario è in grado di bloccare il riconoscimento degli antigeni self e quindi lo sviluppo di risposte autoimmunitarie mediante il mantenimento della tolleranza immunitaria. Tale fenomeno viene sostenuto dall’azione di diverse popolazioni cellulari tolerogeniche, una delle quali è rappresentata cellule soppressorie di derivazione mieloide (MDSC). Le MDSC sono una popolazione molto eterogenea composta da cellule mieloidi immature caratterizzate dalla capacità di sopprimere sia la risposta immunitaria innata che quella adattativa. È stato ipotizzato che in condizioni patologiche, quali infezioni, malattie autoimmunitarie e neoplasie, il rilascio di diversi fattori di crescita induca l’aumento della mielopoiesi ed il blocco maturativo delle cellule mieloidi che si accumulano in uno stato di immaturità. Tali fattori solubili sono inoltre ritenuti coinvolti nella mobilizzazione e nell’attivazione delle MDSC. Le MDSC sono state identificate sia nel modello murino che in pazienti affetti da tumore. Mentre il fenotipo delle MDSC murine è facilmente identificabile mediante l’uso di marcatori specifici (Gr-1, CD11b e IL4Rα), le caratteristiche immunofenotipiche delle MDSC umane non sono ancora state definite. Nonostante questo, sia nel modello murino che nei pazienti affetti da tumore, le MDSC si sono dimostrate avere caratteristiche talvolta granulocitarie e talvolta monocitarie.
In questo lavoro abbiamo dimostrato che è possibile indurre, in vitro, la generazione di MDSC umane a partire da precursori midollari coltivati in presenza di diversi fattori solubili, tra i quali il G-CSF ed il GM-CSF. Il nostro studio ha dimostrato che l’uso combinato di G-CSF e di GM-CSF permette di indurre l’accumulo di cellule mieloidi immature (BM-MDSC) con caratteristiche simili a quelle da noi identificate nel sangue di pazienti affetti da tumore. Le BM-MDSC sono in grado di inibire la proliferazione di linfociti T attivati sia con mitogeni che con allo-antigeni. Inoltre abbiamo dimostrato che la soppressione mediata dalle BM-MDSC è associata sia alla diminuzione dell’espressione delle catene ζ ed ε del CD3 che alla riduzione della produzione di IFN-γ secreto dagli stessi linfociti T.
Considerando l’elevata eterogeneità delle BM-MDSC, in questo lavoro abbiamo cercato di identificare quali sottopopolazioni di BM-MDSC fossero responsabili dall’attività soppressoria. Mediante esperimenti di sorting cellulare abbiamo dimostrato, che le BM-MDSC sono cellule immature ascrivibili ad un preciso stadio di differenziazione. Queste cellule, definite dal fenotipo CD16-/CD11blow/-, presentano infatti caratteristiche morfologiche simili ai promielociti isolati dal midollo ex-vivo ma, a differenza di queste, sono caratterizzate da una minore granulosità, da maggiori dimensioni e dalla capacità si sopprimere la proliferazione linfocitaria accompagnata anche dalla diminuzione dell’espressione della catena ε del CD3 espressa sulla superficie dei linfociti T. Abbiamo inoltre evidenziato l’eterogeneità di questa frazione dimostrando che, al suo interno, si possono identificare altre due sottopopolazioni caratterizzate da una diversa fluorescenza nella lunghezza d’onda del rosso, da una diversa granulosità e da una diversa attività soppressoria.
Nella seconda parte del lavoro ci siamo concentrati sulla valutazione degli effetti della chemioterapia sull’accumulo e sulla funzionalità delle MDSC, una delle principali popolazioni cellulari coinvolte nell’immunosoppressione associata ai tumori e responsabili dell’inefficacia delle terapie immunoterapiche. I dati da noi ottenuti dimostrano che, come osservato nel modello murino, l’aggiunta del 5-fluorouracile a basse dosi è in grado di indurre l’eliminazione dell’attività soppressoria delle BM-MDSC nei confronti dei linfociti T. Queste osservazioni permettono di suggerire il possibile utilizzo di alcuni chemioterapici come adiuvanti nei trattamenti immunoterapici, in quanto in grado di eliminare una delle popolazioni coinvolte nell’immunosoppressione associata ai tumori.

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Tipo di EPrint:Tesi di dottorato
Relatore:Mandruzzato, Susanna
Dottorato (corsi e scuole):Ciclo 23 > Scuole per il 23simo ciclo > ONCOLOGIA E ONCOLOGIA CHIRURGICA
Data di deposito della tesi:NON SPECIFICATO
Anno di Pubblicazione:28 Gennaio 2011
Parole chiave (italiano / inglese):MDSC, immunosoppressione
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/06 Oncologia medica
Struttura di riferimento:Dipartimenti > pre 2012 - Dipartimento di Scienze Oncologiche e Chirurgiche
Codice ID:3722
Depositato il:20 Lug 2011 10:23
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