PM01183 inhibits myeloid-derived suppressor cells in vitro and in vivo

Immunotherapy. 2017 Sep;9(10):805-817. doi: 10.2217/imt-2017-0046.

Abstract

Aim: To evaluate the ability of PM01183 to eliminate myeloid-derived suppressor cells (MDSCs).

Materials & methods: The effect of PM01183 on MDSCs, NK cells and CD8+ T cells was examined in vitro and in vivo. The mechanism by which PM01183 depletes MDSCs was also investigated.

Results: PM01183 reduced the number of MDSCs by inducing apoptosis and attenuated the MDSC-mediated suppression of CD8+ T cells by inhibiting arginase-1 production, whereas no significant effect on CD8+ T or NK cells was noted. The inhibitory effect of PM01183 on MDSC was mediated by the attenuation of STAT3 phosphorylation. The inhibitory effect of PM01183 on MDSCs was greater than those of existing anticancer agents.

Conclusion: PM01183 exhibits strong inhibitory effects on MDSCs.

Keywords: MDSC; NK cells; PM01183; T cells; cancer therapy.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Arginase / metabolism
  • CD8-Positive T-Lymphocytes / immunology*
  • Carbolines / therapeutic use*
  • Cell Line, Tumor
  • Female
  • Heterocyclic Compounds, 4 or More Rings / therapeutic use*
  • Humans
  • Immunosuppression Therapy
  • Killer Cells, Natural / immunology*
  • Lymphocyte Activation / drug effects
  • Mice, Inbred BALB C
  • Mice, Nude
  • Myeloid-Derived Suppressor Cells / drug effects*
  • Myeloid-Derived Suppressor Cells / physiology
  • Phosphorylation
  • STAT3 Transcription Factor / metabolism
  • Uterine Cervical Neoplasms / drug therapy*

Substances

  • Antineoplastic Agents
  • Carbolines
  • Heterocyclic Compounds, 4 or More Rings
  • PM 01183
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • ARG1 protein, human
  • Arginase