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<p>CD8<sup>+</sup> central memory T (T<sub>CM</sub>) cells provide stronger antitumor immunity than more-differentiated effector memory counterparts. Here we show that poly(ADP-ribose) polymerase (PARP) inhibition induces CD8<sup>+</sup> T<sub>CM</sub> cells with superior memory by activating the SIRT-1–FOXO1 pathway and inducing metabolic and transcriptional switches through inhibition of enzymatic activity and enhanced PARP trapping. Together, this results in suppression of the cell cycle and upregulation of memory and fatty acid oxidation gene expression, and reprogramming CD8<sup>+</sup> T cells into T<sub>CM</sub> cells with enhanced metabolic fitness and substantially higher recall capabilities. PARP inhibitor treatment of tumor-bearing mice resulted in an increase in the number of ‘superior T<sub>CM</sub>’ cells within the tumor microenvironment and enhanced immune-mediated antitumor responses. PARP inhibitor-treated CD8<sup>+</sup> T cells were more effective in adoptive cell therapy. Furthermore, the frequency of CD8<sup>+</sup> memory T cells and the expression of their memory markers was increased in patients with cancer treated with PARP inhibitor. Together, these data show that PARP inhibition directly reprograms CD8<sup>+</sup> T cells, enhancing metabolic fitness and generating highly effective therapeutically superior memory cells.</p>

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PARP inhibition generates enhanced CD8+ central memory T cells by transcriptional and metabolic reprogramming

  • 期刊论文

  • 发表日期：

    2026年1月12日

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  • Wael Traboulsi,
  • Pankaj Gaur,
  • Subhadip Kundu,
  • Zainab Ramlaoui,
  • Christopher Priestley-Milianta,
  • Aishwariya Iyengar,
  • Nour Shobaki,
  • Dareen Sarhan,
  • Min-Jung Lee,
  • Jung-Min Lee,
  • George N. Pavlakis,
  • Mikayel Mkrtichyan,
  • Viia E. Valge-Archer,
  • Simon T. Barry,
  • Vivek Verma,
  • Seema Gupta,
  • Samir N. Khleif

摘要

CD8+ central memory T (TCM) cells provide stronger antitumor immunity than more-differentiated effector memory counterparts. Here we show that poly(ADP-ribose) polymerase (PARP) inhibition induces CD8+ TCM cells with superior memory by activating the SIRT-1–FOXO1 pathway and inducing metabolic and transcriptional switches through inhibition of enzymatic activity and enhanced PARP trapping. Together, this results in suppression of the cell cycle and upregulation of memory and fatty acid oxidation gene expression, and reprogramming CD8+ T cells into TCM cells with enhanced metabolic fitness and substantially higher recall capabilities. PARP inhibitor treatment of tumor-bearing mice resulted in an increase in the number of ‘superior TCM’ cells within the tumor microenvironment and enhanced immune-mediated antitumor responses. PARP inhibitor-treated CD8+ T cells were more effective in adoptive cell therapy. Furthermore, the frequency of CD8+ memory T cells and the expression of their memory markers was increased in patients with cancer treated with PARP inhibitor. Together, these data show that PARP inhibition directly reprograms CD8+ T cells, enhancing metabolic fitness and generating highly effective therapeutically superior memory cells.