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

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.

SUBMITTER: Pallavicini I

PROVIDER: S-EPMC11349769 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature

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LSD1 inhibition improves efficacy of adoptive T cell therapy by enhancing CD8<sup>+</sup> T cell responsiveness.

Pallavicini Isabella I Frasconi Teresa Maria TM Catozzi Carlotta C Ceccacci Elena E Tiberti Silvia S Haas Dorothee D Samson Jule J Heuser-Loy Christoph C Nava Lauson Carina B CB Mangione Marta M Preto Elisa E Bigogno Alberto A Sala Eleonora E Iannacone Matteo M Mercurio Ciro C Gattinoni Luca L Caruana Ignazio I Kuka Mirela M Nezi Luigi L Minucci Saverio S Manzo Teresa T

Nature communications 20240827 1

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-bas ...[more]

PMID: 39191730

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Project description:Background: Immune checkpoint blockers (ICBs) are revolutionized therapeutic strategies for cancer, but most patients with solid neoplasms remain resistant to ICBs, partly because of the difficulty in reversing the highly immunosuppressive tumor microenvironment (TME). Exploring the strategies for tumor immunotherapy is highly dependent on the discovery of molecular mechanisms of tumor immune escape and potential therapeutic target. Krüppel-like Factor 5 (KLF5) is a cell-intrinsic oncogene to promote tumorigenesis. However, the cell-extrinsic effects of KLF5 on suppressing the immune response to cancer remain unclear. Methods: We analyzed the immunosuppressive role of KLF5 in mice models transplanted with KLF5-deleted/overexpressing tumor cells. We performed RNA sequencing, immunohistochemistry, western blotting, real time-PCR, ELISA, luciferase assay, chromatin immunoprecipitation (ChIP), and flow cytometry to demonstrate the effects of KLF5 on CD8+ T cell infiltration and related molecular mechanism. Single-cell RNA sequencing and spatial transcriptomics analysis were applied to further decipher the association between KLF5 expression and infiltrating immune cells. The efficacy of KLF5/COX2 inhibitors combined with anti-programmed cell death protein 1 (anti-PD1) therapy were explored in pre-clinical models. Finally, a gene-expression signature depending on KLF5/COX2 axis and associated immune markers was created to predict patient survival. Results: KLF5 inactivation decelerated basal-like breast tumor growth in a CD8+ T-cell-dependent manner. Transcriptomic profiling revealed that KLF5 loss in tumors increases the number and activated function of T lymphocytes. Mechanistically, KLF5 binds to the promoter of the COX2 gene and promotes COX2 transcription; subsequently, KLF5 deficiency decreases prostaglandin E2 (PGE2) release from tumor cells by reducing COX2 expression. Inhibition of the KLF5/COX2 axis increases the number and functionality of intratumoral antitumor T cells to synergize the antitumorigenic effects of anti-PD1 therapy. Analysis of patient datasets at single-cell and spatial resolution shows that low expression of KLF5 is associated with an immune-supportive TME. Finally, we generate a KLF5/COX2-associated immune score (KC-IS) to predict patient survival. Conclusions: Our results identified a novel mechanism responsible for KLF5-mediated immunosuppression in TME, and targeting the KLF5/COX2/PGE2 axis is a critical immunotherapy sensitizer.

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

Publications

LSD1 inhibition improves efficacy of adoptive T cell therapy by enhancing CD8<sup>+</sup> T cell responsiveness.

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

Publications

LSD1 inhibition improves efficacy of adoptive T cell therapy by enhancing CD8<sup>+</sup> T cell responsiveness.

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OmicsDI is part of the ELIXIR infrastructure

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