Purpose The anti-PD-1 and anti-PD-L1 (CIs) checkpoint inhibitors are clinically active in many types of cancer. However, only a minority of patients is a complete and / or long-term clinical picture Answer. We have investigated the effects of different oral data chemotherapies (vinorelbine, cyclophosphamide and 5FU) on local and metastatic the growth of the tumor and the landscape of the circulating immune cells and infiltrating the involved tumor in the CI activity. BALB / c and NSG mice were used for breast (BC) and Vinorelbine B lymphoma, cyclophosphamide and 5-FU (alone or in combination with CI), were administered at metronomic, medium or maximum doses at low tolerable doses. RESULTS Cyclophosphamide increased the circulating MDSC. Vinorelbine, cyclophosphamide and 5-FU Reduced circulating APC. Vinorelbine and cyclophosphamide (medium / high dose) reduced circulating Treg. Cyclophosphamide (at low doses) and 5-FU (at medium doses) Circulating treg slightly higher. Cyclophosphamide was the most potent drug in reducing circulating CD3 + CD8 + and CD3 + CD4 + cells. Vinorelbine, cyclophosphamide and 5- FU have reduced the number of circulating B cells, with cyclophosphamide showing the most potent effect. Vinorelbine reduced circulating NK, while cyclophosphamide e 5-FU, at low doses, increased circulating NK. Despite the reduced circulation T, B and NK effector cells, preclinical synergy was observed between chemotherapeutic and anti-PDL1. Combination regimes more effective in the case of neoplastic lesions enriched in B cells, and, in mice carrying BC (but not in mice with lymphoma), also in NK cells. Conclusions Vinorelbine, cyclophosphamide and 5-FU have preclinical effects based on circulation and immune cells infiltrating the tumor and can be used to achieve synergy with anti-PD-L1.
Scopo Gli inibitori del checkpoint anti-PD-1 e anti-PD-L1 (CIs) sono clinicamente attivi in molti tipi di cancro. Tuttavia, solo una minoranza di pazienti raggiunge un quadro clinico completo e / o di lunga durata. Abbiamo studiato gli effetti di diverse dosi di 3 ampiamente utilizzate, attive per via orale chemioterapici (vinorelbina, ciclofosfamide e 5FU) su locali e metastatici la crescita del tumore e il paesaggio delle cellule immuni circolanti e infiltranti il tumore coinvolte nell'attività CI. I topi BALB / c e NSG sono stati utilizzati per generare modelli di cancro al seno (BC) e Linfoma a cellule B Vinorelbina, ciclofosfamide e 5-FU (da soli o in combinazione con IC), sono stati somministrati a dosaggi metronomici, medi o massimi a basse dosi tollerabili. risultati La ciclofosfamide aumentava la MDSC circolante. Vinorelbina, ciclofosfamide e 5-FU APC circolanti ridotti. Vinorelbina e ciclofosfamide (a dosi medio / alte) ridotto Treg circolanti. Ciclofosfamide (a basse dosi) e 5-FU (a medie dosi) Treg circolanti leggermente aumentato. La ciclofosfamide era il farmaco più potente nel ridurre le cellule CD3 + CD8 + e CD3 + CD4 + circolanti. Vinorelbina, ciclofosfamide e 5- FU hanno ridotto il numero di cellule B circolanti, con ciclofosfamide che mostra l'effetto più potente. Vinorelbina ha ridotto NK circolanti, mentre ciclofosfamide e 5-FU, a basse dosi, aumentati NK circolanti. Nonostante la ridotta circolazione T, B e NK cellule effettrici, sinergia preclinica è stata osservata tra chemioterapici e anti-PDL1. Regimi combinatori più efficaci in caso di lesioni neoplastiche arricchito in cellule B, e, in topi portatori di BC (ma non in topi con linfoma), anche in cellule NK. conclusioni Vinorelbina, ciclofosfamide e 5-FU hanno effetti preclinici significativi sulla circolazione e cellule immunitarie infiltranti il tumore e possono essere utilizzate per ottenere sinergia con anti-PD-L1.
Effetti della Vinorelbina, Ciclofosfamide e 5-FU sulle cellule immunitarie circolanti e infiltranti tumore, migliorano l'efficacia di anti-PD-L1 nel carcinoma mammario e nel linfoma in modelli murini.
FALLANCA, FABIOLA
2016/2017
Abstract
Purpose The anti-PD-1 and anti-PD-L1 (CIs) checkpoint inhibitors are clinically active in many types of cancer. However, only a minority of patients is a complete and / or long-term clinical picture Answer. We have investigated the effects of different oral data chemotherapies (vinorelbine, cyclophosphamide and 5FU) on local and metastatic the growth of the tumor and the landscape of the circulating immune cells and infiltrating the involved tumor in the CI activity. BALB / c and NSG mice were used for breast (BC) and Vinorelbine B lymphoma, cyclophosphamide and 5-FU (alone or in combination with CI), were administered at metronomic, medium or maximum doses at low tolerable doses. RESULTS Cyclophosphamide increased the circulating MDSC. Vinorelbine, cyclophosphamide and 5-FU Reduced circulating APC. Vinorelbine and cyclophosphamide (medium / high dose) reduced circulating Treg. Cyclophosphamide (at low doses) and 5-FU (at medium doses) Circulating treg slightly higher. Cyclophosphamide was the most potent drug in reducing circulating CD3 + CD8 + and CD3 + CD4 + cells. Vinorelbine, cyclophosphamide and 5- FU have reduced the number of circulating B cells, with cyclophosphamide showing the most potent effect. Vinorelbine reduced circulating NK, while cyclophosphamide e 5-FU, at low doses, increased circulating NK. Despite the reduced circulation T, B and NK effector cells, preclinical synergy was observed between chemotherapeutic and anti-PDL1. Combination regimes more effective in the case of neoplastic lesions enriched in B cells, and, in mice carrying BC (but not in mice with lymphoma), also in NK cells. Conclusions Vinorelbine, cyclophosphamide and 5-FU have preclinical effects based on circulation and immune cells infiltrating the tumor and can be used to achieve synergy with anti-PD-L1.È consentito all'utente scaricare e condividere i documenti disponibili a testo pieno in UNITESI UNIPV nel rispetto della licenza Creative Commons del tipo CC BY NC ND.
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https://hdl.handle.net/20.500.14239/23629