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Solito, Samantha (2010) Cellule soppressorie di derivazione mieloide: espansione nei pazienti con tumore, induzione in vitro con fattori di crescita ed analisi dei meccanismi molecolari coinvolti nell'immunosoppressione. [Tesi di dottorato]

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Abstract (inglese)

Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of cells that expands during cancer, inflammation and infection and are potent inhibitors of T-cell-mediated antitumor immunity. MDSC accumulate in the blood, lymph nodes and bone marrow and at tumor sites in most patients and experimental animals with cancer and inhibit both adaptative and innate immunity. Expansion, mobilization and activaction of MDSC is driven by tumors-secreted growth factors, and by a profound alteration of myelopoiesis.

In cancer patients the nature of MDSC is still poorly defined since evidence exists for both monocytic and granulocytic features. In the present study we evaluated the phenotype and the suppressive activity of leukocyte subsets freshly isolated from the blood of melanoma and colon cancer patients. Our results indicate that cells with characteristics of MDSC can be found in both mononuclear and polymorphonuclear fraction, and that a useful marker for their identification is the alpha chain of IL4R.

Subsequently, we defined growth factors able to generate MDSC in vitro from human bone marrow precursors and to use these cells to characterize better the biology and phenotype of human MDSC. We demonstrated that combinations of some cytokine, such as G-CSF, GM-CSF and IL-6 induce the expansion of bone-marrow immature myeloid populations (BM-MDSC) expressing IL4Ra, with phenotype and inhibitory activity comparable to patients' MDSC. Functional assays revealed that only cytokine-treated bone marrow cells are able to suppress lymphocyte proliferation, while ex-vivo isolated cells and untreated bone marrow cells do not interfere significantly with T lymphocyte proliferation. BM-MDSC suppress activation of both alloactivated and mitogen activated T lymphocytes.

We further examined BM-MDSC mechanisms of suppression, and we demonstrated that these cells are able to suppress lymphocyte proliferation by decreasing lymphocyte CD3z chain expression and that suppression requires cell-to-cell contact. Immunoregulatory activity of BM-MDSC is dependent on C/EBPb transcription factor, a key component of the emergency myelopoiesis, because the knock down of C/EBPb leads to a marked decrease in the immunosuppressive activity of BM-MDSC.

Since BM-derived MDSC consist of a heterogeneous myeloid population, we separated myeloid fractions with immunomagnetic sorting and we demonstrated that the Lineage negative fraction of BM-MDSC contains the main immunosuppressive activity by inducing a decrease of lymphocyte proliferation and of CD3z expression.

Abstract (italiano)

Le cellule soppressorie di derivazione mieloide (MDSC) costituiscono una popolazione molto eterogenea che viene espansa in alcune condizioni patologiche, come le neoplasie, le infiammazioni e le infezioni ed ha la capacità di inibire potentemente l'immunità antitumorale mediata dai linfociti T. Le MDSC si accumulano nel sangue, nei linfonodi, nel midollo osseo e nel microambiente tumorale, in pazienti ed in modelli animali portatori di tumore e inibiscono sia la risposta immunitaria innata, che quella adattativa. L'espansione, la mobilizzazione e l'attivazione delle MDSC è indotta da fattori di crescita rilasciati della cellule tumorali e da un'estesa alterazione della mielopoiesi.

In pazienti portatori di tumore la caratterizzazione fenotipica e funzionale delle MDSC non è ancora completamente definita, ma esistono evidenze sia sulla natura granulocitaria che su quella monocitaria di tale popolazione. In questo lavoro di tesi abbiamo valutato il fenotipo e l'attività soppressoria di popolazioni leucocitarie isolate dal sangue periferico di pazienti affetti da tumore del colon e melanoma. I nostri risultati indicano che cellule con caratteristiche delle MDSC possono essere trovate sia nella frazione monocitaria che in quella granulocitaria e che un marcatore utile per la loro identificazione è la catena alpha del recettore dell'interleuchina 4 (IL4Ra).

Nella seconda parte di questo lavoro abbiamo definito i fattori di crescita necessari per l'induzione in vitro di MDSC da progenitori mieloidi midollari, ed abbiamo usato tali cellule per caratterizzare la biologia ed il fenotipo delle MDSC. Abbiamo dimostrato che le combinazioni di alcune citochine, come G-CSF, GM-CSF e IL-6 inducono l'espansione di popolazioni mieloidi immature midollari (BM-MDSC) che esprimono IL4Ra e dotate di caratteristiche fenotipiche e funzionali simili a quelle delle MDSC espanse nei pazienti. I saggi funzionali hanno mostrato che solo le cellule trattate con le citochine sono in grado di inibire la proliferazione linfocitaria, mentre le cellule isolate ex-vivo o le colture mantenute in vitro senza l'aggiunta dei fattori di crescita, non interferiscono in modo significativo con la proliferazione linfocitaria.
Le MDSC derivate da midollo (BM-MDSC) sopprimono sia la proliferazione dei linfociti attivati da alloantigeni, che la proliferazione di linfociti attivati da mitogeni.
Abbiamo quindi analizzato i meccanismi di soppressione delle BM-MDSC ed abbiamo dimostrato che tali cellule sono in grado di sopprimere la proliferazione linfocitaria inducendo una diminuzione dell'espressione della catena z del CD3 e che la soppressione mediata dalle BM-MDSC richiede il contatto cellula-cellula. L'attività immunoregolatrice delle BM-MDSC dipende dal fattore di trascrizione C/EBPb, un componente chiave della granulopoiesi di emergenza, dal momento che la diminuzione della proteina induce una marcata inibizione dell'attività soppressoria delle BM-MDSC.

Infine abbiamo separato alcune sottopopolazioni mieloidi presenti nelle BM-MDSC, poichè queste sono rappresentate da una popolazione mieloide eterogenea, ed abbiamo dimostrato che la frazione cellulare Lineage- è responsabile della maggiore attività immunosoppressoria inducendo una diminuzione della proliferazione linfocitaria e dell'espressione del CD3z di superficie.

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Tipo di EPrint:Tesi di dottorato
Relatore:Mandruzzato, Susanna
Dottorato (corsi e scuole):Ciclo 22 > Scuole per il 22simo ciclo > ONCOLOGIA E ONCOLOGIA CHIRURGICA
Data di deposito della tesi:NON SPECIFICATO
Anno di Pubblicazione:29 Gennaio 2010
Parole chiave (italiano / inglese):soppressione, tolleranza, BM-MDSC
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:2772
Depositato il:29 Set 2010 11:19
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