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Immunosuppressive Effects of Multiple Myeloma-Derived Extracellular Vesicles Through T Cell Exhaustion

Shinya Hagiwara1, Masaki Ri1,2, Toru Ebina1

  • 1Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences and Medical School, Nagoya, Japan.

Cancer Science
|May 9, 2025
PubMed

Insights

Multiple myeloma (MM) extracellular vesicles (EVs) suppress T cell activity by increasing immune checkpoint markers. This contributes to the immune-suppressive tumor environment, impairing anti-cancer immune responses.

Area of Science:

  • Immunology
  • Oncology
  • Cell Biology

Background:

  • Extracellular vesicles (EVs) play roles in tumor progression, including angiogenesis and drug resistance in multiple myeloma (MM).
  • The function of MM-derived EVs in modulating the immune system, particularly T cell exhaustion, remains largely unclear.

Purpose of the Study:

  • To investigate the impact of MM-derived EVs on T cell exhaustion markers.
  • To identify specific proteins within MM EVs that contribute to immune suppression.

Main Methods:

  • Treatment of activated peripheral blood mononuclear cells (PBMCs) from healthy donors with MM-derived EVs.
  • Analysis of immune checkpoint marker expression on CD8+ T cells.
  • Proteomic analysis of MM-derived EVs.

Main Results:

  • MM-derived EVs induced immunosuppressive effects, upregulating immune checkpoint markers on CD8+ T cells.
  • Proteomic analysis revealed proteins like IL-8, SLC1A5, PIN2, and FSP1 associated with T cell exhaustion and inflammation.
  • Sphingosine kinase 1 (SPHK1) was found to be enriched in MM EVs, suggesting its role in SPHK1/S1P signaling-mediated immunosuppression.

Conclusions:

  • MM-derived EVs promote T cell exhaustion by upregulating immune checkpoint markers.
  • These EVs contribute to the immune-suppressive microenvironment in MM, leading to diminished T cell activity.
  • Targeting SPHK1/S1P signaling could be a potential therapeutic strategy against MM-induced immune suppression.
Keywords:
T‐cell exhaustionextracellular vesiclesimmune checkpoint proteinsmultiple myelomasphingosine kinase 1

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