The contribution of the monocyte-macrophage lineage to immunotherapy outcomes

Abstract Macrophages execute core functions in maintaining tissue homeostasis, in which their extensive plasticity permits a spectrum of functions from tissue remodeling to immune defense. 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 hematopoietic 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 CSF1 receptor (CSF1R) to induce macrophage depletion showed remarkable capacity to prevent fibrosis in preclinical models and has subsequently demonstrated impressive efficacy for improving 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 chimeric antigen receptor 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 contextualize 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 signaling axis, for therapeutic benefit in the context of both cellular and immunotherapy.