Epigenetic control of macrophage polarization: implications for targeting tumor-associated macrophages.

Amber E De Groot,Kenneth J Pienta

doi:10.18632/oncotarget.24556

Amber E De Groot, Kenneth J Pienta

Open Access

https://doi.org/10.18632/oncotarget.24556

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Journal: Oncotarget	Publication Date: Feb 21, 2018
Citations: 81	License type: cc-by

Affiliation: Johns Hopkins University, Johns Hopkins Medicine

Abstract

The progression of cancer is a result of not only the growth of the malignant cells but also the behavior of other components of the tumor microenvironment (TME). Tumor-associated macrophages (TAMs) are key components of the TME that influence tumor growth and disease progression. TAMs can either inhibit or support tumor growth depending on their polarization to classically-activated macrophages (M1s) or alternatively-activated macrophages (M2s), respectively. Epigenetic regulation plays a significant role in determining this polarization and manipulating the epigenetic regulation in macrophages would provide a means for selectively targeting M2s thereby eliminating tumor-supporting TAMs while sparing tumor-inhibiting M1 TAMs. Many pharmacologic modulators of epigenetic enzymes are currently used clinically and could be repurposed for treating tumors with high TAM infiltrate. While much research involving epigenetic enzymes and their modulators has been performed in M1s, significantly less is known about the epigenetic regulation of M2s. This review highlights the field’s current knowledge of key epigenetic enzymes and their pharmacologic modulators known to influence macrophage polarization.

Highlights

Despite significant advancements over the years, cancer remains the second leading cause of death in the US with an estimated 600,920 cancer-related deaths and 1,688,780 new cancer cases in the US in 2017 [1]
The interactions between tumor cells and the tumor microenvironment (TME) are analogous to ecosystem interactions and crosstalk between tumor cells and non-malignant cells within the TME create supporting networks that are critical for determining disease severity [2,3,4,5]
While this study revealed JMJD3 to be unnecessary for M1 polarization of TLR ligandstimulated mouse peritoneal macrophages, other studies involving IFNg-stimulated human monocytederived macrophages (HMDMs) [27] or LPS + IFNγstimulated HMDMs from rheumatoid arthritis patients [30] detail its role in inducing pro-inflammatory cytokine expression

Summary

Introduction

Despite significant advancements over the years, cancer remains the second leading cause of death in the US with an estimated 600,920 cancer-related deaths and 1,688,780 new cancer cases in the US in 2017 [1]. As our understanding of the disease improves, it has become clear that the progression of disease is dependent on the growth of the malignant cells and on the behavior of all components of the tumor microenvironment (TME). The interactions between tumor cells and the TME are analogous to ecosystem interactions and crosstalk between tumor cells and non-malignant cells within the TME create supporting networks that are critical for determining disease severity [2,3,4,5]. Despite the effectiveness of current therapies which focus on targeting malignant cells, patients continue to recur. Research has suggested that the TME plays a critical role in recurrence [6, 7]. Cancer research has expanded to include efforts to target TME components and supportive networks [8, 9]

Objectives

Conclusion