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Measuring Mitochondrial Function of Naïve and Effector CD8 T Cells
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Stat5 opposes the transcription factor Tox and rewires exhausted CD8+ T cells toward durable effector-like states

Jean-Christophe Beltra1, Mohamed S Abdel-Hakeem2, Sasikanth Manne3

  • 1Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USA; Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA, USA.

Immunity
|December 13, 2023
PubMed

Insights

Rewiring exhausted CD8+ T cells involves reprogramming their epigenetic landscape. Activating Stat5 antagonizes Tox, promoting durable effector and NK-like states with anti-tumor potential.

Area of Science:

  • Immunology
  • Cell Biology
  • Cancer Research

Background:

  • Exhausted CD8+ T cells (Tex) are a major hurdle in cancer immunotherapy.
  • Tex cells undergo epigenetic programming by the transcription factor Tox.
  • Epigenetic plasticity exists across Tex progenitor (Texprog), intermediate (Texint), and terminal (Texterm) subsets.

Purpose of the Study:

  • To investigate epigenetic transitions between Tex cell subsets.
  • To identify molecular circuits governing Tex cell functional states.
  • To explore therapeutic strategies for rewiring exhausted T cells.

Main Methods:

  • Analysis of epigenetic remodeling during Tex cell subset transitions.
  • Investigation of the interplay between Stat5a and Tox transcription factors.
  • Utilizing an orthogonal IL-2:IL2Rβ-pair for temporal Stat5 activity induction.
  • Assessing anti-tumor potential and polyfunctionality of reprogrammed T cells.

Main Results:

  • A reciprocal antagonistic circuit between Stat5a and Tox was identified.
  • Stat5 promotes Texint cell formation and effector biology during Texprog-to-Texint transition.
  • Constitutive Stat5a activity antagonizes Tox, leading to durable effector/NK-like CD8+ T cells.
  • Temporal Stat5 induction enhances Texint accumulation, especially with PD-L1 blockade.
  • Stat5 re-engagement partially reverses exhaustion epigenetics and restores polyfunctionality.

Conclusions:

  • The IL-2-Stat5 axis offers a therapeutic target for rewiring exhausted T cells.
  • Manipulating Stat5 can promote durable anti-tumor immunity.
  • Rewiring Tex cells toward functional states presents a promising cancer immunotherapy strategy.
Keywords:
CD8(+) T cellIL-2PD-1 blockadeStat5Tex intermediateToxepigenetic reprogrammingexhaustionorthogonal IL-2:IL2Rβ

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