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BCL2 inhibition stimulates dendritic cell function for improved anticancer immunotherapy

Genes & Immunity (2024)Cite this article

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Abstract

Recently we developed a dendritic cell (DC) genotype-phenotype screening platform that is based on CRISPR/Cas9-mediated gene editing of immortalized DC precursors. Whole genome screening for gain-of-function phenotypes led to the identification of BCL2 as a DC-specific immune checkpoint. Genetic or pharmacological inhibition of BCL2 similarly enhanced the antigen presentation capacity of conventional type-1 dendritic cells (cDC1) and mediated T cell-dependent anticancer immunity. The therapeutic anticancer efficacy of the BCL2 inhibitor venetoclax in mice was further increased when combined with a PD-1-targeted immune checkpoint inhibitor. In sum, we delineated a novel strategy of dual checkpoint blockade for cancer immunotherapy in which improvement of DC antigen presentation and avoidance of T cell exhaustion can be advantageously combined.

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Fig. 1: Dendritic cell antigen presentation and T cell activation.

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Acknowledgements

OK receives funding from Institut National du Cancer (INCa) and Association pour la recherche sur le cancer (ARC); GK is supported by the Ligue contre le Cancer (équipe labellisée); Agence National de la Recherche (ANR) – Projets blancs; AMMICa US23/CNRS UMS3655; ARC; Cancéropôle Ile-de-France; Fondation pour la Recherche Médicale (FRM); a donation by Elior; Equipex Onco-Pheno-Screen; European Joint Programme on Rare Diseases (EJPRD); European Research Council Advanced Investigator Award (ERC-2021-ADG, ICD-Cancer, Grant No. 101052444), European Union Horizon 2020 Projects Oncobiome, Prevalung (grant No. 101095604) and Crimson; Institut National du Cancer (INCa); Institut Universitaire de France; LabEx Immuno-Oncology (ANR-18-IDEX-0001); a Cancer Research ASPIRE Award from the Mark Foundation; the RHU Immunolife; Seerave Foundation; SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); and SIRIC Cancer Research and Personalized Medicine (CARPEM). This study contributes to the IdEx Université de Paris ANR-18-IDEX-0001. Views and opinions expressed are those of the author(s) only and do not necessarily reflect those of the European Union, the European Research Council or any other granting authority. Neither the European Union nor any other granting authority can be held responsible for them. Figure was generated with BioRender.com.

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Authors and Affiliations

  1. Centre de Recherche des Cordeliers, Equipe Labellisée par la Ligue Contre le Cancer, Université de Paris Cité, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France

    Peng Liu, Liwei Zhao, Guido Kroemer & Oliver Kepp

  2. Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Center, Villejuif, France

    Peng Liu, Liwei Zhao, Guido Kroemer & Oliver Kepp

  3. Department of Biology, Institut du Cancer Paris CARPEM, Hôpital Européen Georges Pompidou, AP-HP, Paris, France

    Guido Kroemer

Authors
  1. Peng Liu
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  2. Liwei Zhao
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  3. Guido Kroemer
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  4. Oliver Kepp
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Contributions

PL and LZ summarized date and designed display items, OK and GK wrote the manuscript.

Corresponding authors

Correspondence to Guido Kroemer or Oliver Kepp.

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Competing interests

OK and GK have been holding research contracts with Daiichi Sankyo, Eleor, Kaleido, Lytix Pharma, PharmaMar, Osasuna Therapeutics, Samsara Therapeutics, Sanofi, Tollys, and Vascage. GK is on the Board of Directors of the Bristol Myers Squibb Foundation France. GK is a scientific co-founder of everImmune, Osasuna Therapeutics, Samsara Therapeutics and Therafast Bio. OK is a scientific co-founder of Samsara Therapeutics. GK is in the scientific advisory boards of Hevolution, Institut Servier and Longevity Vision Funds and Rejuveron Life Sciences. GK is the inventor of patents covering therapeutic targeting of aging, cancer, cystic fibrosis and metabolic disorders. GK’s brother, Romano Kroemer, was an employee of Sanofi and now consults for Boehringer-Ingelheim. The funders had no role in the design of the study; in the writing of the manuscript, or in the decision to publish the results.

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Liu, P., Zhao, L., Kroemer, G. et al. BCL2 inhibition stimulates dendritic cell function for improved anticancer immunotherapy. Genes Immun (2024). https://doi.org/10.1038/s41435-024-00256-9

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  • DOI: https://doi.org/10.1038/s41435-024-00256-9

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