Inhibition of the Histone Methyltransferase EZH2 Enhances Protumor Monocyte Recruitment in Human Mesothelioma Spheroids

Abstract

Malignant pleural mesothelioma (MPM) is a highly aggressive cancer with a long latency period and dismal prognosis. Recently, tazemetostat (EPZ-6438), an inhibitor of the histone methyltransferase EZH2, has entered clinical trials due to the antiproliferative effects reported on MPM cells. However, the direct and indirect effects of epigenetic reprogramming on the tumor microenvironment are hitherto unexplored. To investigate the impact of tumor-associated macrophages (TAMs) on MPM cell responsiveness to tazemetostat, we developed a three-dimensional MPM spheroid model that recapitulates in vitro, both monocytes’ recruitment in tumors and their functional differentiation toward a TAM-like phenotype (Mo-TAMs). Along with an increased expression of genes for monocyte chemoattractants, inhibitory immune checkpoints, immunosuppressive and M2-like molecules, Mo-TAMs promote tumor cell proliferation and spreading. Prolonged treatment of MPM spheroids with tazemetostat enhances both the recruitment of Mo-TAMs and the expression of their protumor phenotype. Therefore, Mo-TAMs profoundly suppress the antiproliferative effects due to EZH2 inhibition in MPM cells. Overall, our findings indicate that TAMs are a driving force for MPM growth, progression, and resistance to tazemetostat; therefore, strategies of TAM depletion might be evaluated to improve the therapeutic efficacy of pharmacological inhibition of EZH2.

Immune activation is essential for the antitumor activity of EZH2 inhibition in urothelial carcinoma

“…5 ). This result might be explained by a non–cell autonomous mechanism of action of the inhibitor potentially promoting innate immune cells functions in the absence of a functional adaptive immune system ( 43 ). This will be an intriguing line of investigation for future studies.…”

Regulation of CCL2 by EZH2 affects tumor-associated macrophages polarization and infiltration in breast cancer

“…Suppressing EZH2 activity by EZH2 inhibitor GSK126 resulted in more myeloid-derived suppressor cells (MDSC) and less CD4 + and IFNγ + CD8 + T cells accumulated in tumors, which are key components of anti-tumor immunity, suggesting that EZH2 inhibitors may exhibit antitumor efficacy by modulating tumor immune microenvironment [ 58 ]. Recent study reports that EZH2 inhibitor EPZ-6438 triggers malignant pleural mesothelioma cells to express high level of different monocytes chemoattractants, including CCL2 and CSF1, which lead to increased monocytes recruitment in tumor spheroids as well as M2 TAMs differentiation [ 59 ]. However, the role of EZH2 in breast cancer development by affecting macrophage polarization has not been uniformly determined.…”

Emerging role of EZH2 in rheumatic diseases: A comprehensive review

“…Monocyte is a kind of immune cell in innate immunity 26,27 . There is high expression of EZH2 in tumor tissues, which may regulate recruitment, proliferation, and activation of monocytes 28–32 . EZH2 was highly expressed in peripheral blood monocytes of pediatric pneumonia patients, and there was up‐regulated apoptosis of monocytes 33 .…”