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Selective inhibition of mTORC1 in tumor vessels increases antitumor immunity

Shan Wang1,2, Ariel Raybuck3, Eileen Shiuan4

  • 1Veterans Affairs Medical Center, Tennessee Valley Healthcare System, Nashville, Tennessee, USA.

JCI Insight
|August 8, 2020
PubMed

Insights

Low-dose mTORC1 inhibitors normalize tumor blood vessels, enhancing anti-tumor immunity. This approach selectively targets endothelial cells, improving cancer treatment efficacy without harming immune cells.

Area of Science:

  • Oncology
  • Immunology
  • Vascular Biology

Background:

  • Tumor blood vessels influence cancer progression and treatment response.
  • Mammalian target of rapamycin complex 1 (mTORC1) is crucial in angiogenesis.
  • Current mTORC1 inhibitors have limitations in solid tumors due to side effects and compensatory signaling.

Purpose of the Study:

  • To investigate the efficacy of low-dose mTORC1 inhibition in normalizing tumor vasculature.
  • To determine the impact of endothelial-specific mTORC1 inhibition on anti-tumor immunity.
  • To explore endothelial mTORC1 as a therapeutic target for enhancing cancer immunotherapy.

Main Methods:

  • Utilized low-dose RAD001 (everolimus) and targeted inducible gene ablation of Raptor in endothelial cells (RaptorECKO) in mouse models.
  • Assessed tumor vessel normalization, immune cell infiltration (lymphocytes, dendritic cells), tumor growth, and metastasis.
  • Investigated the role of granulocyte-macrophage colony-stimulating factor (GM-CSF) and T cells in the observed anti-tumor effects.
  • Analyzed human tumor datasets to validate findings.

Main Results:

  • Low-dose RAD001 selectively inhibited mTORC1 in endothelial cells, normalizing tumor vessels without affecting tumor or immune cells.
  • RaptorECKO mice exhibited increased tumor-infiltrating lymphocytes via GM-CSF-mediated CD103+ dendritic cell activation.
  • Tumor growth and metastasis were significantly reduced in RaptorECKO mice.
  • GM-CSF neutralization or T cell depletion abrogated the anti-tumor effects, confirming their importance.

Conclusions:

  • Endothelial mTORC1 is a viable target for tumor vessel normalization.
  • Targeting endothelial mTORC1 enhances anti-tumor immunity and reduces tumor progression.
  • This strategy holds potential for improving the efficacy of cancer immunotherapies.
Keywords:
Cancer immunotherapyImmunologyOncologyendothelial cells

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