Every year, over a million people are diagnosed with blood cancers around the globe. Many patients still face poor prognoses due the persistence of therapy-resistant cancer cells and disease relapse. Despite significant investment into the development of novel anti-cancer therapies that can induce cancer cell death, how the immune system deals with the mass of dying cancer cells after therapy remains unclear. The swift removal of dead cells is a fundamental process necessary to prevent damaging inflammation. Thus, understanding the dynamic interplay between dying cancer cells and phagocytes is vital to develop novel immunotherapies.
Haematological malignancies including acute myeloid leukemia and lymphomas rapidly proliferate in tissues such as the bone marrow. To study the in vivo dynamics of these blood cancers, we paired our world-class intravital imaging approach of the bone marrow calvarium with elegant models to track cancer and immune cell subsets in vivo. We performed comprehensive in vivo imaging and monitored the immediate and multiday response of blood cancer cells post-therapy. For the first time, we visualised and characterised the in vivo recognition and efferocytosis of dying cancer cells by phagocytes in the bone marrow microenvironment. We demonstrated that this process is an extremely rapid event, performed in concert by a variety of phagocytic cell types. Despite being significantly outnumbered, phagocytes can cope with the mass of dying blood cancer cells post-therapy through mechanisms of serial engulfment. Our multiday imaging analysis also revealed small clusters of cancer cells within the bone marrow microenvironment that could evade therapy-induced death and immune recognition. Moreover, by tracking the bone marrow after ceasing therapy, we demonstrated that these clusters lead to disease relapse and convey therapeutic resistance.
Together, our study has provided several exciting advances for the field of cell death and cancer biology. It has revealed important spatial and kinetic insights into the immune cell response and cell death post anti-cancer therapy. This exciting new knowledge may create a foundation to improve novel immunotherapies.