The Contribution of the Monocyte-Macrophage Lineage to Immunotherapy Outcomes

Macrophages execute core functions in maintaining tissue homeostasis, where their extensive plasticity permits a spectrum of functions from tissue remodelling to immune defence. However, perturbations to tissue-resident macrophages during disease, and the subsequent emergence of monocyte-derived macrophages, can hinder tissue recovery and promote further damage through inflammatory and fibrotic programs. Gaining a fundamental understanding of the critical pathways defining pathogenic macrophage populations enables the development of targeted therapeutic approaches to improve disease outcomes. In the setting of chronic graft-versus-host disease (cGVHD), which remains the major complication of allogeneic haematopoietic stem cell transplantation, colony-stimulating factor 1 (CSF1)-dependent donor-derived macrophages have been identified as key pathogenic mediators of fibrotic skin and lung disease. Antibody blockade of the CSF1R to induce macrophage depletion showed remarkable capacity to prevent fibrosis in pre-clinical models and has subsequently demonstrated impressive efficacy for improving fibrotic cGVHD in ongoing clinical trials. Similarly, macrophage depletion approaches are currently under investigation for their potential to augment responses to immune checkpoint inhibition. Moreover, both monocyte and tissue-resident macrophage populations have recently been implicated as mediators of the numerous toxicities associated with CAR T-cell therapy, further highlighting potential avenues of macrophage-based interventions to improve clinical outcomes. Herein, we examine the current literature on basic macrophage biology and contextualise this in the setting of cellular and immunotherapy. Additionally, we highlight mechanisms by which macrophages can be targeted, largely by interfering with the CSF1/CSF1R signalling axis, for therapeutic benefit in the context of both cellular and immunotherapy.