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The BCL2 inhibitor venetoclax mediates anticancer effects through dendritic cell activation

Cell Death & Differentiation volume 30, pages 2447–2451 (2023)Cite this article

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Abstract

BCL2 is an apoptosis-inhibitory oncoprotein that also possesses apoptosis-unrelated activities. Pharmacological BCL2 inhibitors have been developed with the scope of driving BCL2-dependent cancer cells into apoptosis, and one BCL2 antagonist, venetoclax, has been clinically approved for the treatment of specific leukemias and lymphomas. Nonetheless, it appears that venetoclax, as well as genetic BCL2 inhibition, can mediate anticancer effects through an indirect action. Such an indirect effect relies on the enhancement of the immunostimulatory function of dendritic cells, hence increasing tumor immunosurveillance. Mechanistically, BCL2 inhibition involves improved antigen presentation by conventional type-1 dendritic cells (cDC1s) due to the activation of an interferon response, leading to a T cell-mediated anticancer immune response that can be further enhanced by PD-1 blockade. These findings support the emerging hypothesis that successful antineoplastic drugs generally mediate their effects indirectly, through the immune system, rather via merely cell-autonomous effects on malignant cells.

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Fig. 1: Mechanisms of anticancer effects of venetoclax against solid cancers.
Fig. 2: Cascade of molecular, cellular and immunological events linking the inhibition of BCL2 to the stimulation of anticancer immune responses in vivo.

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Acknowledgements

OK receives funding from Institut National du Cancer (INCa); GK is supported by the Ligue contre le Cancer (équipe labellisée); Agence National de la Recherche (ANR) – Projets blancs; AMMICa US23/CNRS UMS3655; Association pour la recherche sur le cancer (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.

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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, Oliver Kepp & Guido Kroemer

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

    Peng Liu, Liwei Zhao, Oliver Kepp & Guido Kroemer

  3. Gustave Roussy Cancer Campus, Villejuif, France

    Laurence Zitvogel

  4. Institut National de la Santé Et de la Recherche Médicale (INSERM) UMR 1015, ClinicObiome, Equipe Labellisée-Ligue Nationale contre le Cancer, Villejuif, France

    Laurence Zitvogel

  5. Center of Clinical Investigations in Biotherapies of Cancer (BIOTHERIS) 1428, Villejuif, France

    Laurence Zitvogel

  6. Université Paris-Saclay, Gif-sur-Yvette, France

    Laurence Zitvogel

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

    Guido Kroemer

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

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Correspondence to Oliver Kepp or Guido Kroemer.

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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. LZ has held research contracts with Glaxo Smyth Kline, Incyte, Lytix, Kaleido, Innovate Pharma, Daiichi Sankyo, Pilege, Merus, Transgene, 9 m, Tusk and Roche, was on the on the Board of Directors of Transgene, is a cofounder of everImmune, and holds patents covering the treatment of cancer and the therapeutic manipulation of the microbiota. 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. 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., Zitvogel, L. et al. The BCL2 inhibitor venetoclax mediates anticancer effects through dendritic cell activation. Cell Death Differ 30, 2447–2451 (2023). https://doi.org/10.1038/s41418-023-01232-y

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