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LSD1 inhibition improves efficacy of adoptive T cell therapy by enhancing CD8 + T cell responsiveness.

Isabella PallaviciniTeresa Maria FrasconiCarlotta CatozziElena CeccacciSilvia TibertiDorothee HaasJule SamsonChristoph HeuserCarina B Nava LausonMarta MangioneElisa PretoAlberto BigognoEleonora SalaMatteo IannaconeCiro MercurioLuca GattinoniIgnazio CaruanaMirela KukaLuigi NeziSaverio MinucciTeresa Manzo
Published in: Nature communications (2024)
The lysine-specific histone demethylase 1 A (LSD1) is involved in antitumor immunity; however, its role in shaping CD8 + T cell (CTL) differentiation and function remains largely unexplored. Here, we show that pharmacological inhibition of LSD1 (LSD1i) in CTL in the context of adoptive T cell therapy (ACT) elicits phenotypic and functional alterations, resulting in a robust antitumor immunity in preclinical models in female mice. In addition, the combination of anti-PDL1 treatment with LSD1i-based ACT eradicates the tumor and leads to long-lasting tumor-free survival in a melanoma model, complementing the limited efficacy of the immune or epigenetic therapy alone. Collectively, these results demonstrate that LSD1 modulation improves antitumoral responses generated by ACT and anti-PDL1 therapy, providing the foundation for their clinical evaluation.
Keyphrases
  • cell therapy
  • stem cells
  • mesenchymal stem cells
  • free survival
  • clinical evaluation
  • dna methylation
  • type diabetes
  • metabolic syndrome
  • insulin resistance
  • bone marrow
  • combination therapy
  • replacement therapy