Abstract

Macrophages are a specialized class of innate immune cells with multifaceted roles in modulation of the inflammatory response, homeostasis, and wound healing. While developmentally derived or originating from circulating monocytes, naïve macrophages can adopt a spectrum of context-dependent activation states ranging from pro-inflammatory (classically activated, M1) to pro-wound healing (alternatively activated, M2). Tumors are known to exploit macrophage polarization states to foster a tumor-permissive milieu, particularly by skewing macrophages toward a pro-tumor (M2) phenotype. These pro-tumoral macrophages can support cancer progression by several mechanisms including immune suppression, growth factor production, promotion of angiogenesis and tissue remodeling. By preventing the adoption of this pro-tumor phenotype or reprogramming these macrophages to a more pro-inflammatory state, it may be possible to inhibit tumor growth. Here, we describe types of tumor-derived signaling that facilitate macrophage reprogramming, including paracrine signaling and activation of innate immune checkpoints. We also describe intervention strategies targeting macrophage plasticity to limit disease progression and address their implications in cancer chemo- and immunotherapy.

Highlights

  • Macrophages represent one of the most phenotypically diverse innate immune cell populations

  • We explore potential conceptual flaws in the current pro-inflammatory/pro-wound healing paradigm in cancer, based on recent single-cell RNA-seq findings, and implications these could have in the manipulation of macrophage activation state to reduce tumor growth

  • Given the contrasting nature of ATP versus ADO signaling for macrophage activation in tumor immunity, this interface serves as a potential target for the clearance of tumor cells

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Summary

INTRODUCTION

Macrophages represent one of the most phenotypically diverse innate immune cell populations. They are key homeostatic regulators that activate and modulate the innate and, subsequent adaptive immune response to infectious agents and host-derived components. Much like other innate immune cells, they are hard-wired to respond to cues rather than being “educated” to elicit a response, as is the case of adaptive immune cells [1]. Macrophages are equipped with a variety of Pattern Recognition Receptors (PRRs) that, once activated, trigger pre-determined programs in response to environmental stimuli. Some pro-inflammatory stimuli include Pathogen-Associated Molecular Patterns (PAMPs), cellular or chemical moieties derived from pathogens, or DamageAssociated Molecular Patterns (DAMPs) which are released by damaged cells and malignancies

Mechanisms of Macrophage Plasticity
Src family tyrosine kinases
Phase IV clinical trials FDA approved for CML Phase I
Macrophage Polarization by Targeting Intracellular Signaling Mechanisms
Targeting Innate Immune Checkpoints to Improve Therapeutic Outcomes
Characterization of Macrophage Activation State in Tumors
OPEN QUESTIONS IN MACROPHAGE PLASTICITY DURING CANCER
Findings
AUTHOR CONTRIBUTIONS
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