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

Int J Mol Sci. 2021 Apr 22;22(9):4391. doi: 10.3390/ijms22094391.

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.

Keywords: EPZ-6438; EZH2; epigenetic reprogramming; malignant pleural mesothelioma; monocytes; spheroids; tazemetostat; tumor microenvironment; tumor-associated macrophages.

MeSH terms

  • Benzamides / pharmacology*
  • Biphenyl Compounds / pharmacology*
  • Cell Proliferation
  • Enhancer of Zeste Homolog 2 Protein / antagonists & inhibitors*
  • Humans
  • Mesothelioma / drug therapy
  • Mesothelioma / metabolism
  • Mesothelioma / pathology*
  • Monocytes / drug effects
  • Monocytes / pathology*
  • Morpholines / pharmacology*
  • Pyridones / pharmacology*
  • Spheroids, Cellular / drug effects
  • Spheroids, Cellular / pathology*
  • Tumor Cells, Cultured
  • Tumor Microenvironment
  • Tumor-Associated Macrophages / drug effects
  • Tumor-Associated Macrophages / pathology*

Substances

  • Benzamides
  • Biphenyl Compounds
  • Morpholines
  • Pyridones
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein
  • tazemetostat