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Temsirolimus Enhances Anti-Cancer Immunity by Inducing Autophagy-Mediated Degradation of the Secretion of Small

Seong-Sik Park1, Jong-In Kim1, Chan-Hyeong Lee1

  • 1Department of Molecular Medicine, CMRI, Exosome Convergence Research Center (ECRC), School of Medicine, Kyungpook National University, Daegu 41944, Korea.

Cancers
|September 9, 2022
PubMed

Insights

Temsirolimus (TEM) inhibits tumor-derived small extracellular vesicle (sEV) PD-L1 and cellular PD-L1, enhancing immune checkpoint blockade therapy (ICBT) effectiveness. This novel approach boosts T cell activity against cancer by reducing PD-L1 immune suppression.

Area of Science:

  • Immunology
  • Oncology
  • Cell Biology

Background:

  • Tumor-derived small extracellular vesicle (sEV) programmed death-ligand 1 (PD-L1) impairs immune checkpoint blockade therapy (ICBT) by binding to PD-1 on immune cells.
  • Current therapies lack agents that inhibit both sEV PD-L1 secretion and cellular PD-L1 to enhance anti-cancer immunity.

Purpose of the Study:

  • To investigate the potential of temsirolimus (TEM) in inhibiting both sEV PD-L1 and cellular PD-L1 levels in MDA-MB-231 breast cancer cells.
  • To evaluate TEM's role in modulating autophagy and its impact on sEV secretion.
  • To assess the combined efficacy of TEM and anti-PD-L1 antibodies in enhancing anti-cancer immunity.

Main Methods:

  • MDA-MB-231 cells were treated with temsirolimus (TEM) to analyze its effect on PD-L1 expression and autophagy.
  • Autophagy activation by TEM was studied through the degradation of multivesicular bodies (MVBs).
  • Co-culture systems and immunocompetent mouse models of breast cancer were used to evaluate anti-cancer immunity and the effects of combination therapy.

Main Results:

  • TEM treatment led to the degradation of MVBs via autophagy, reducing sEV PD-L1 secretion.
  • TEM promoted CD8+ T cell-mediated anti-cancer immunity in co-cultures.
  • Combination therapy with TEM and anti-PD-L1 antibodies significantly enhanced CD4+ and CD8+ T cell responses in vivo, an effect reversed by exogenous sEV PD-L1.

Conclusions:

  • Temsirolimus (TEM) effectively inhibits both tumor-derived sEV PD-L1 and cellular PD-L1.
  • TEM can overcome resistance to ICBT by modulating autophagy and reducing PD-L1-mediated immune suppression.
  • The combination of TEM with anti-PD-L1 antibodies represents a promising strategy to enhance anti-cancer immunity in breast cancer.
Keywords:
PD-L1autophagyimmunotherapysmall extracellular vesicletemsirolimus

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