Dependence on mitochondrial respiration of malignant T cells reveals a new therapeutic target for angioimmunoblastic T-cell lymphoma
Creators
- Krug, Adrien
- Mhaidly, Rana
- Tosolini, Marie
- Mondragon, Laura
- Tari, Gamze
- Turtos, Adriana
- Paul-Bellon, Rachel
- Asnafi, Vahid
- Marchetti, Sandrine
- Di Mascio, Léa
- Travert, Marion
- Bost, Frédéric
- Bachy, Emmanuel
- Argüello, Rafael
- Fournié, Jean-Jacques
- Gaulard, Philippe
- Lemonnier, François
- Ricci, Jean-Ehrland
- Verhoeyen, Els
Contributors
Others:
- Centre méditerranéen de médecine moléculaire (C3M) ; Université Nice Sophia Antipolis (1965 - 2019) (UNS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UniCA)
- Equipe labellisée Ligue contre le Cancer
- Centre de Recherches en Cancérologie de Toulouse (CRCT) ; Université Toulouse III - Paul Sabatier (UT3) ; Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
- Molecular virology and immunology – Physiopathology and therapeutic of chronic viral hepatitis (Team 18) (Inserm U955) ; Institut Mondor de Recherche Biomédicale (IMRB) ; Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)
- Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)) ; Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)
- Hospices Civils de Lyon (HCL)
- Centre d'Immunologie de Marseille - Luminy (CIML) ; Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Description
Cancer metabolic reprogramming has been recognized as one of the cancer hallmarks that promote cell proliferation, survival, as well as therapeutic resistance. Up-to-date regulation of metabolism in T-cell lymphoma is poorly understood. In particular, for human angioimmunoblastic T-cell lymphoma (AITL) the metabolic profile is not known. Metabolic intervention could help identify new treatment options for this cancer with very poor outcomes and no effective medication. Transcriptomic analysis of AITL tumor cells, identified that these cells use preferentially mitochondrial metabolism. By using our preclinical AITL mouse model, mimicking closely human AITL features, we confirmed that T follicular helper (Tfh) tumor cells exhibit a strong enrichment of mitochondrial metabolic signatures. Consistent with these results, disruption of mitochondrial metabolism using metformin or a mitochondrial complex I inhibitor such as IACS improved the survival of AITL lymphoma-bearing mice. Additionally, we confirmed a selective elimination of the malignant human AITL T cells in patient biopsies upon mitochondrial respiration inhibition. Moreover, we confirmed that diabetic patients suffering from T-cell lymphoma, treated with metformin survived longer as compared to patients receiving alternative treatments. Taking together, our findings suggest that targeting the mitochondrial metabolic pathway could be a clinically efficient approach to inhibit aggressive cancers such as peripheral T-cell lymphoma.
Abstract
International audienceAdditional details
Identifiers
- URL
- https://amu.hal.science/hal-04780921
- URN
- urn:oai:HAL:hal-04780921v1
Origin repository
- Origin repository
- UNICA