Trained innate immunity attenuates macrophage efferocytosis of cancer cells

Macrophage phagocytosis has been implicated in regulating anti-tumour immunity. Trained innate immunity (TII), inducedviamodulation of mature myeloid cells or their bone marrow progenitors, 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 requires further elucidation. Here, we investigated whether macrophage phagocytosis of tumour cells can be modulated through induction of TII.

To this end, mice were pre-treated with β-glucan, a fungal-derived agonist of TII, 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.

While TII did not have any impact in the modulation of ADCP, efferocytosis was decreased in trained macrophages. Along the same line, gene expression analysis demonstrated that mRNA levels of molecules promoting efferocytosis were downregulated in trained macrophages. Trained macrophages exerted decreased levels of active caspase-1 and produced decreased levels of interleukin-1β upon efferocytosis of tumour cells.

Our findings reveal a hitherto unknown role of TII in the regulation of anti-tumour immunity and may set the stage for designing new cancer immunotherapeutic approaches targeting macrophage efferocytosis.