Macrophage phagocytosis of tumour cells is modulated by trained innate immunity

Cancer represents the second leading cause of death having long-lasting socioeconomic impact. There is an increasing need to better understand disease pathogenesis to inform the development of therapeutic approaches and to address the timely question of how to increase the efficacy of current immunotherapies. Macrophages in solid tumours display hallmarks of cancer and their role is critical in shaping the balance between pro-tumour and anti-tumour responses. One of their major effector functions, named phagocytosis, has been implicated in regulating anti-tumour immunity. Trained innate immunity (TII) is induced via modulation of mature myeloid cells or their bone marrow progenitors and mediates sustained increased responsiveness to secondary challenges. Despite the advances in the study of TII-mediated anti-tumour activity, the impact of TII on the orchestration of phagocytosis in the tumour setting warrants further elucidation. This thesis investigated whether macrophage-dependent phagocytosis of tumour cells can be modulated through TII induction.To assess phagocytosis, mice were pre-treated with the fungal-derived TII inducer β-glucan and bone marrow was isolated for macrophage differentiation. Macrophages were then co-cultured with tumour cells that were either apoptotic or opsonised with an antibody recognising a tumour antigen, to mimic efferocytosis and antibody-dependent cellular phagocytosis (ADCP), respectively.TII did not have any impact on the modulation of ADCP. Interestingly, efferocytosis was decreased in macrophages from mice pre-treated with β-glucan, which was associated with reduced levels of active caspase-1 and the subsequent release of the IL-1β cytokine. Similarly, the mRNA levels of molecules promoting efferocytosis were down-regulated in macrophages from the β-glucan group. Combined in vitro treatment of macrophages from mice pre-treated with β-glucan and a commercially available MerTK tyrosine kinase inhibitor further decreased efferocytosis.Considering that efferocytosis has been linked to tumour progression, this study may aid in improving existing cancer immunotherapies by modulating efferocytosis through induction of TII.