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<p>Reprogramming T cell metabolism can improve intratumoural fitness. By performing a CRISPR/Cas9 metabolic survey in CD8<sup>+</sup> T cells, we identified 83 targets and we applied single-cell RNA sequencing to disclose transcriptome changes associated with each metabolic perturbation in the context of pancreatic cancer. This revealed elongation of very long-chain fatty acids protein 1 (<i>Elovl1</i>) as a metabolic target to sustain effector functions and memory phenotypes in CD8<sup>+</sup> T cells. Accordingly, <i>Elovl1</i> inactivation in adoptively transferred T cells combined with anti-PD-1 showed therapeutic efficacy in resistant pancreatic and melanoma tumours. The accumulation of saturated long-chain fatty acids in <i>Elovl1</i>-deficient T cells destabilized INSIG1, leading to SREBP2 activation, increased plasma membrane cholesterol and stronger T cell receptor signalling. <i>Elovl1</i>-deficient T cells increased mitochondrial fitness and fatty acid oxidation, thus withstanding the metabolic stress imposed by the tumour microenvironment. Finally, <i>ELOVL1</i> in CD8<sup>+</sup> T cells correlated with anti-PD-1 response in patients with melanoma. Altogether, <i>Elovl1</i> targeting synergizes with anti-PD-1 to promote effective T cell responses.</p>

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A functional single-cell metabolic survey identifies Elovl1 as a target to enhance CD8+ T cell fitness in solid tumours

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月10日

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  • Samantha Pretto,
  • Qian Yu,
  • Pierre Bourdely,
  • Sarah Trusso Cafarello,
  • Heleen H. Van Acker,
  • Joren Verelst,
  • Elena Richiardone,
  • Lotte Vanheer,
  • Amir Roshanzadeh,
  • Franziska Schneppenheim,
  • Charlotte Cresens,
  • Maria Livia Sassano,
  • Jonas Dehairs,
  • Martin Carion,
  • Shehab Ismail,
  • Patrizia Agostinis,
  • Susana Rocha,
  • Tobias Bald,
  • Johan Swinnen,
  • Cyril Corbet,
  • Sophia Y. Lunt,
  • Bernard Thienpont,
  • Mario Di Matteo,
  • Massimiliano Mazzone

摘要

Reprogramming T cell metabolism can improve intratumoural fitness. By performing a CRISPR/Cas9 metabolic survey in CD8+ T cells, we identified 83 targets and we applied single-cell RNA sequencing to disclose transcriptome changes associated with each metabolic perturbation in the context of pancreatic cancer. This revealed elongation of very long-chain fatty acids protein 1 (Elovl1) as a metabolic target to sustain effector functions and memory phenotypes in CD8+ T cells. Accordingly, Elovl1 inactivation in adoptively transferred T cells combined with anti-PD-1 showed therapeutic efficacy in resistant pancreatic and melanoma tumours. The accumulation of saturated long-chain fatty acids in Elovl1-deficient T cells destabilized INSIG1, leading to SREBP2 activation, increased plasma membrane cholesterol and stronger T cell receptor signalling. Elovl1-deficient T cells increased mitochondrial fitness and fatty acid oxidation, thus withstanding the metabolic stress imposed by the tumour microenvironment. Finally, ELOVL1 in CD8+ T cells correlated with anti-PD-1 response in patients with melanoma. Altogether, Elovl1 targeting synergizes with anti-PD-1 to promote effective T cell responses.