Characterization of mechanisms that compromise dendritic cell function in melanoma
- Autores: Xavier Catena Parrado
- Directores de la Tesis: María Soledad Soengas González (dir. tes.)
- Lectura: En la Universidad Autónoma de Madrid ( España ) en 2021
- Idioma: inglés
- Número de páginas: 148
- Títulos paralelos:
- Caracterización de mecanismos que comprometen la función de las células dendríticas en el melanoma
- Tribunal Calificador de la Tesis: David Sancho Madrid (presid.), Manuel Valiente Cortes (secret.), Alena Gros Vidal (voc.)
- Programa de doctorado: Programa de Doctorado en Biociencias Moleculares por la Universidad Autónoma de Madrid
- Materias:
- Enlaces
- Tesis en acceso abierto en: Biblos-e Archivo
- Resumen
Cutaneous melanoma is characterized by its high metastatic potential and strong capacity to evade immune surveillance. Immunotherapies are currently the most successful treatment for metastatic melanoma. Unfortunately, still, a large portion of patients are resistant or acquire resistance after several months. Resistance to immunotherapy is a complex mechanism with many factors being involved. Some of these mechanisms of resistance target antigen-presenting cells (APCs), which are in charge of establishing efficient anticancer immune responses. The most specialized APC are dendritic cells (DCs). Melanoma can impact DCs by two main mechanisms, by excluding them from the primary lesion, or by impairing their essential functions. Altogether, these strategies lead to a dysfunctional and/or attenuated antitumor T cell-mediated response. Defining new factors that control DC function is fundamental to improve patient prognosis and response to immune therapy.
This Doctoral Thesis aimed to characterize the strategies by which melanoma modify DC development and function and define the impact of these cells on cancer development and therapy. In particular, we focused on the heparin-binding factor MIDKINE (MDK), which we have found that promotes lymphangiogenesis and metastasis, as well as resistance to immunotherapy mediated by suppressive macrophages. Here we pursued a more comprehensive analysis of the immune profile controlled by MDK by using a combination of proteomic, transcriptomic, computational, and functional analyses.
In this PhD Thesis, we have unveiled the impact of MDK on DCs at four levels. First, we found that MDK reduced DC infiltration in melanoma and lymphoid organs by blocking their differentiation while favoring monocyte/granulocyte fate. Second, we have observed that MDK inhibited DC-mediated antigen presentation by blocking their main functions such as phagocytosis, activation, and presentation. Consequently, MDK-educated DCs prompted a dysfunctional T response that poorly controlled tumor growth and inefficiently responded to therapy. Third, we described an ALK-mediated activation of STAT3 and inhibition of NF-κB-MAPK signaling as putative downstream effectors of MDK in DCs. Finally, we characterized the influence of the host’s MDK on cancer biology. To achieve this, we used the Mdk-deficient mice in the context of immune activation and cancer immunity. Our initial results indicate that lack of MDK could favor the activation of DCs and other myeloid cells that ultimately support a better response to cancer. Together, this PhD Thesis uncovered novel roles of the melanoma secreted MDK, which hinder anticancer immune response by interfering with dendritic cell biology while establishing a tolerogenic environment that facilitates resistance to immunotherapy. As MDK is overexpressed in a variety of immune-related pathologies, our results may hold translational relevance beyond cancer
