Monocyte-mediated infiltration and iron oxide nanoparticle uptake in adrenocortical carcinoma: Mechanisms, interactions, and therapeutic implications

Adrenocortical carcinoma (ACC) is a rare, aggressive malignancy characterized by limited treatment options and poor survival rates. This thesis explores the role of monocyte/macrophage infiltration and iron oxide nanoparticle (IONP) uptake in ACC, examining their potential therapeutic implications. Using immunohistochemistry and transcriptomic analysis, this study demonstrated substantial macrophage infiltration in ACC tissues, predominantly exhibiting an immunosuppressive M2 phenotype. High levels of M0 macrophages correlated with poorer patient outcomes, whereas elevated M2 macrophages showed an unexpected positive association with survival, suggesting complex roles in tumour progression and immune modulation. Further investigations revealed differential recruitment and functional polarization of peripheral monocytes by ACC cells via chemokine-driven mechanisms, particularly involving the CCL2-CCR2 axis. Monocytes/Macrophages interactions significantly modulated ACC cell proliferation and responsiveness to mitotane treatment, highlighting their potential role in therapeutic resistance. Additionally, this research assessed the potential of IONPs as theranostic agents. ACC cells exhibited concentration and time-dependent nanoparticle uptake, primarily through macropinocytosis, without substantial impairment of cellular steroidogenesis or viability at therapeutically relevant concentrations. Notably, nanoparticle uptake dynamics were significantly influenced by interactions with endothelial cells and primary monocytes, suggesting competitive internalization pathways. Collectively, these findings underscore the intricate interplay between monocytes/macrophages and ACC cells, emphasizing the importance of the tumour microenvironment in disease progression and treatment response. This work advances understanding of ACC pathophysiology and provides a foundation for developing XIII targeted therapies and nanoparticle-based theranostic.

Funder

Science Foundation Ireland

Publisher

University of Galway

Rights

CC BY-NC-ND

cbn

Collections

University of Galway Theses (PhD Theses)