Innovative therapies targeting tumor-microenvironment crosstalk in indolent B-cell non-Hodgkin lymphomas
[eng] Follicular Lymphoma (FL) and Chronic Lymphocytic Leukemia (CLL) share several features in common: 1) they are indolent B-cell neoplasms, 2) patients usually relapse after treatment, 3) both pathologies as yet remain incurable. The initial driving event in both malignancies is the early acquisi...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2016 |
| País: | España |
| Institución: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/109026 |
| Acceso en línea: | https://hdl.handle.net/2445/109026 |
| Access Level: | acceso abierto |
| Palabra clave: | Limfomes Leucèmia limfocítica crònica Lymphomas Chronic lymphocytic leukemia |
| Sumario: | [eng] Follicular Lymphoma (FL) and Chronic Lymphocytic Leukemia (CLL) share several features in common: 1) they are indolent B-cell neoplasms, 2) patients usually relapse after treatment, 3) both pathologies as yet remain incurable. The initial driving event in both malignancies is the early acquisition of genetic alterations; however, the proliferative drive for malignant cells is largely dependent on external signals from the tumor microenvironment, which favor the survival of malignant cells. For this reason, the main aim of this thesis was to explore new therapies targeting the interactions between the tumor cell and its microenvironment in FL and CLL. For the work in FL, we chose to use the Follicular Dendritic Cell (FDC) line HK, isolated from human tonsils. The results obtained indicate that the microenvironment in FL, and more specifically FDCs, can profoundly modify the FL transcriptome by activating different pathways among that: angiogenesis, migration, adhesion and serum-like responses. Then, it was demonstrated that the PI3K pathway is a common signaling mediator of the identified pathways and may constitute a good target for therapy in this setting. The results obtained demonstrated that PI3K inhibition by buparlisib significantly reduced FDC- induced expression and secretion of proangiogenic factors in FL cells and also reduced vasculature formation in vivo. Moreover, it was demonstrated that buparlisib hampers FDC-derived serum-like responses and survival signaling. It was also uncovered that FDCs increase the motility properties of FL cells and consequently lymphoma dissemination, by two complementary mechanisms: first, by increasing the expression of adhesion molecules, which favor the adhesion of FL cells to the extracellular matrix (ECM), and second, by secreting chemotactic molecules such as CXCL12. Buparlisib also shows inhibitory activity in this scenario; on the one hand, it reduces FL adhesion to ECM, and reduces CXCL12 secretion and induced migration and signaling. Moreover, buparlisib shows in vivo activity in subcutaneous and systemic mouse models. In summary, this work demonstrates that FDCs contribute to FL lymphomagenesis trough the modulation of a plethora of events leading to lymphoma growth and dissemination, and how the inhibition of PI3K/AKT axis could interfere with this crosstalk and constitute a valuable therapeutic tool. For the work in CLL we chose to work with daratumumab, an anti-CD38 monoclonal antibody CD38 expression is dynamic and regulated by the tumor microenvironment, and is considered a negative prognostic marker for CLL. The results obtained with daratumumab show that it induces lysis of CLL cells mainly via Antibody-Dependent Cellular Cytotoxicity (ADCC) and Antibody-Dependent Cellular Phagocytosis (ADCP) in the presence of external effectors both in vitro and in vivo. However, daratumumab is not able to engage significant Complement-Dependent Cytotoxicity (CDC) on CLL cells. Daratumumab activity may extend beyond its effect on the tumor cells, as we have demonstrated its potential to counteract microenvironment-derived signaling in protective cancer niches, such as lymph nodes and bone marrow. In this context, daratumumab interferes with in vitro cell migration and in vivo homing of CLL cells to spleen in NSG mice. Moreover, daratumumab interferes with transendothelial migration and organ invasion of malignant cells by significantly reducing CD49d/CD29-mediated adhesion to VCAM-1, indicating that daratumumab treatment may impede CLL tissue infiltration that leads to progressive disease. Daratumumab also demonstrated impressive in vivo activity in a CLL systemic mouse model, where it prevented tumor progression and significantly improved overall survival. Taken together, daratumumab immunotherapy opens a new horizon as a novel therapeutic approach for CD38+ CLL by not only inducing the classical antibody-mediated cytotoxicity but also by harnessing microenvironment-derived survival signaling and blocking CLL dissemination to secondary lymphoid organs. |
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