Monocytes and macrophages in cancer: investigating their potential as disease biomarkers and therapeutic targets

[eng] Cancer is the leading cause of death worldwide, with lung and liver cancers being major contributors. Liver cancer is often preceded by cirrhosis, considered as the final stage of chronic liver disease. Recognizing the crucial role of the immune system in cancer, ongoing research focuses on improving immunotherapy effectiveness to benefit a broader patient population. Circulating monocytes and tumor-associated macrophages (TAMs) play key roles in the immune response, contributing to tumor progression, treatment outcomes, and survival in various cancers, including lung and liver. TAMs are the most abundant immune cells in the tumor microenvironment (TME). They can adopt either a pro-inflammatory (M1) or immunosuppressive (M2) phenotype, with the M2 correlating with poorer survival outcomes in cancers. Current research is exploring TAM reprogramming as a novel cancer immunotherapy, with monoclonal antibodies offering safer and more effective alternatives to chemotherapy. On the other hand, monocytes are promising biomarker candidates due to their diverse phenotype and accessibility. The two main objectives of this thesis were to investigate the role of macrophage secreted protein CD5L expression in TAMs in lung and liver cancers, contributing to the development of a new CD5L-targeted immunotherapy, and to analyze the proteome of circulating monocytes in cirrhosis and liver cancer to identify new biomarkers and altered biological pathways occurring in hepatocellular carcinoma (HCC). We show that CD5L expression in TAMs is linked to poor prognosis in papillary lung adenocarcinoma (PAC) and HCC. Additionally, targeting CD5L in a mouse model reduced tumor size and reprogrammed the TME into a pro-inflammatory state. We also discovered deregulated pathways affecting monocyte activity in cirrhosis and HCC, and identified a new cell receptor panel as a potential blood-based biomarker for HCC. These findings mark significant progress in creating a novel anticancer immunotherapy that induces beneficial changes in the TME and identifying a promising biomarker for HCC detection.