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Hypoxia-adapted Multiple Myeloma Stem Cells Resist γδ-T-Cell-mediated Killing by Modulating the Mevalonate Pathway

Yusuke Sano1, Naoko Kuwabara2, Saori Nakagawa2

  • 1Department of Clinical and Translational Physiology, Kyoto Pharmaceutical University, Kyoto, Japan.

Anticancer Research
|January 25, 2023
PubMed
Abstract

Insights

Multiple myeloma stem cells are resistant to new treatments. Researchers found that hypoxia-adapted multiple myeloma stem cells have lower isopentenyl pyrophosphate levels, reducing their susceptibility to gamma delta T cell attacks.

Area of Science:

  • Immunology
  • Oncology
  • Biochemistry

Background:

  • Multiple myeloma (MM) prognosis has improved with new therapies, but it remains incurable due to resistant MM stem cells.
  • Hypoxia-adapted MM cells (MM-HA) exhibit stem-cell-like properties, posing a therapeutic challenge.
  • Gamma delta (γδ) T cells target tumor cells via butyrophilin (BTN) 3A1/2A1, dependent on isopentenyl pyrophosphate (IPP) accumulation.

Purpose of the Study:

  • To investigate the efficacy of γδ T cells against MM stem-like cells.
  • To determine the role of the mevalonate pathway and IPP accumulation in MM stem cell resistance.

Main Methods:

  • Utilized flow cytometry, liquid chromatography-tandem mass spectrometry, and western blotting.
  • Assessed γδ T cell cytotoxicity against MM-HA cells and MM cells under normoxic conditions (MM-Normo).
  • Quantified IPP levels in MM-HA cells and their supernatants.

Main Results:

  • γδ T cell cytotoxicity was significantly lower against MM-HA cells compared to MM-Normo cells.
  • MM-HA cells showed reduced intracellular IPP concentrations.
  • Expression of key mevalonate pathway enzymes (mevalonate decarboxylase, farnesyl diphosphate synthase) was decreased in MM-HA cells.

Conclusions:

  • Reduced IPP accumulation, driven by mevalonate pathway modulation in MM-HA cells, suppresses γδ T cell-mediated cytotoxicity.
  • Targeting the mevalonate pathway in MM stem cells may be a strategy to enhance immunotherapy effectiveness.
Keywords:
Multiple myelomahypoxiaisopentenyl pyrophosphatemevalonate pathwaymyeloma stem-like cellsγδ T cells

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