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

Isabella Pallavicini, Teresa Maria Frasconi, Carlotta Catozzi, Elena Ceccacci, Silvia Tiberti, Dorothee Haas, Jule Samson, Christoph Heuser-Loy, Carina B. Nava Lauson, Marta Mangione, Elisa Preto, Alberto Bigogno, Eleonora Sala, Matteo Iannacone, Ciro Mercurio, Luca Gattinoni, Ignazio Caruana, Mirela Kuka, Luigi Nezi, Saverio Minucci and Teresa Manzo ()
Additional contact information
Isabella Pallavicini: Department of Experimental Oncology
Teresa Maria Frasconi: Department of Experimental Oncology
Carlotta Catozzi: Department of Experimental Oncology
Elena Ceccacci: Department of Experimental Oncology
Silvia Tiberti: Department of Experimental Oncology
Dorothee Haas: Oncology and Stem Cell Transplantation Unit- University Hospital of Würzburg
Jule Samson: Oncology and Stem Cell Transplantation Unit- University Hospital of Würzburg
Christoph Heuser-Loy: Leibniz Institute for Immunotherapy
Carina B. Nava Lauson: Department of Experimental Oncology
Marta Mangione: Department of Experimental Oncology
Elisa Preto: Department of Experimental Oncology
Alberto Bigogno: Department of Experimental Oncology
Eleonora Sala: Vita-Salute San Raffaele University
Matteo Iannacone: Vita-Salute San Raffaele University
Ciro Mercurio: the FIRC Institute of Molecular Oncology IFOM
Luca Gattinoni: Leibniz Institute for Immunotherapy
Ignazio Caruana: Oncology and Stem Cell Transplantation Unit- University Hospital of Würzburg
Mirela Kuka: Vita-Salute San Raffaele University
Luigi Nezi: Department of Experimental Oncology
Saverio Minucci: Department of Experimental Oncology
Teresa Manzo: Department of Experimental Oncology

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-51500-9

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