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TSC2 regulates tumor susceptibility to TRAIL-mediated T-cell killing by orchestrating mTOR signaling

Chun-Pu Lin1, Joleen J H Traets1,2, David W Vredevoogd1

  • 1Division of Molecular Oncology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands.

The EMBO Journal
|January 30, 2023
PubMed

Insights

Tuberous Sclerosis Complex 2 (TSC2) depletion enhances cancer cell death from T-cell attacks by disrupting tumor cell survival pathways. This finding reveals TSC2 as a key regulator in cancer immunotherapy response.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Cancer immunotherapy resistance limits clinical success.
  • Understanding mechanisms of tumor immune evasion is critical.

Purpose of the Study:

  • To investigate the role of Tuberous Sclerosis Complex 2 (TSC2) in melanoma cell susceptibility to cytotoxic T lymphocyte (CTL) killing.
  • To elucidate the molecular mechanisms underlying TSC2's function in anti-tumor immunity.

Main Methods:

  • Whole-genome CRISPR-Cas9 screening in human melanoma cells.
  • Analysis of mTOR signaling pathway dynamics post-CTL attack.
  • In vitro and in vivo functional assays.
  • TCGA patient data analysis for TSC2 and TRAIL signaling correlation.

Main Results:

  • TSC2 depletion sensitized melanoma cells to CTL-mediated killing by disrupting mTOR regulation and promoting apoptosis.
  • Wild-type cells adapted to CTL attack via altered mTORC2 activity, enhancing survival.
  • TSC2 inactivation upregulated TRAIL receptor expression, enhancing tumor cell death.
  • Clinical data showed a negative correlation between TSC2 expression and TRAIL signaling, and a lower TSC2 immune signature in responders to immune checkpoint blockade.

Conclusions:

  • TSC2 plays a critical role in protecting tumor cells from CTL attack.
  • TSC2 regulates the crosstalk between TSC2-mTOR and TRAIL signaling pathways.
  • Targeting TSC2 may represent a novel therapeutic strategy to enhance cancer immunotherapy efficacy.
Keywords:
T-cell sensitivityTRAILTSC2mTORtumor cells

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