Developing a co-culture system for the study of macrophage function and its therapeutic potential in acute myeloid leukaemia

Abstract

Acute myeloid leukaemia (AML) is a complex haematological disorder involving AML cells' interactions with their microenvironment. Macrophages, which play an integral role in innate immunity, have been extensively studied in solid cancers. However, their roles in leukaemogenesis are presently unclear. This project aims to reveal the interactions between leukaemic cells and macrophages in the context of two commonly found mutations in a variety of cell line models. In RAS-mutated AML, macrophages were shown to suppress leukaemia growth in a phagocytosisindependent manner. An average of twenty percent reduction in total cell number was consistently found in all RAS-mutated cells. In TP53-mutated AML, more phagocytic macrophages were enumerated when they were co-cultured with TP53 mutant compared to the wild type (WT) cell lines. Co-culture results reflected thatii macrophages could suppress leukaemia growth by phagocytosing the leukemic cells in short term. Furthermore, macrophage’s response to specific AML treatment in vitro appeared to correlate with their in vivo response. In addition, this study developed an in vitro system to examine macrophage function and its therapeutic potential in AML. Decitabine and PLK4 inhibitor CFI-400495 showed efficacy in the co-culture system and were later found to act synergistically with anti-CD47 antibody. The in vitro platform arising from this study might shed light on the understanding of macrophage function during leukaemogenesis and provide a screening platform for the identification of anti-leukaemia therapy that acts via activation of innate immunity.