Iron Boosts Antitumor Type 1 T-cell Responses and Anti-PD1 Immunotherapy

Author:

Porte Sarah1ORCID,Audemard-Verger Alexandra23ORCID,Wu Christian1ORCID,Durand Aurélie1ORCID,Level Théo1ORCID,Giraud Léa1ORCID,Lombès Amélie1ORCID,Germain Mathieu1ORCID,Pierre Rémi1ORCID,Saintpierre Benjamin1ORCID,Lambert Mireille1ORCID,Auffray Cédric1ORCID,Peyssonnaux Carole1ORCID,Goldwasser François4ORCID,Vaulont Sophie1ORCID,Alves-Guerra Marie-Clotilde1ORCID,Dentin Renaud1ORCID,Lucas Bruno1ORCID,Martin Bruno1ORCID

Affiliation:

1. Université Paris-Cité, Institut Cochin, Centre National de la Recherche Scientifique (CNRS) UMR8104, Institut National de la Santé et de la Recherche Médicale (INSERM) U1016, Paris, France. 1

2. Department of Internal Medicine, CHU de Tours, Tours, France. 2

3. University of Tours, Tours, France. 3

4. Department of Medical Oncology, Cochin Hospital, Paris Cancer Institute CARPEM, Université Paris Cité, APHP.Centre, Paris, France. 4

Abstract

Abstract Cancers only develop if they escape immunosurveillance, and the success of cancer immunotherapies relies in most cases on their ability to restore effector T-cell functions, particularly IFNγ production. Revolutionizing the treatment of many cancers, immunotherapies targeting immune checkpoints such as PD1 can increase survival and cure patients. Unfortunately, although immunotherapy has greatly improved the prognosis of patients, not all respond to anti-PD1 immunotherapy, making it crucial to identify alternative treatments that could be combined with current immunotherapies to improve their effectiveness. Here, we show that iron supplementation significantly boosts T-cell responses in vivo and in vitro. The boost was associated with a metabolic reprogramming of T cells in favor of lipid oxidation. We also found that the “adjuvant” effect of iron led to a marked slowdown of tumor cell growth after tumor cell line transplantation in mice. Specifically, our results suggest that iron supplementation promotes antitumor responses by increasing IFNγ production by T cells. In addition, iron supplementation improved the efficacy of anti-PD1 cancer immunotherapy in mice. Finally, our study suggests that, in patients with cancer, the quality and efficacy of the antitumor response following anti-PD1 immunotherapy may be modulated by plasma ferritin levels. In summary, our results suggest the benefits of iron supplementation on the reactivation of antitumor responses and support the relevance of a fruitful association between immunotherapy and iron supplementation.

Funder

Ligue Contre le Cancer

Fondation ARC pour la Recherche sur le Cancer

Groupement des Entreprises Françaises dans la lutte contre le Cancer

Institut National de la Santé et de la Recherche Médicale

Centre National de la Recherche Scientifique

Université Paris Descartes

Publisher

American Association for Cancer Research (AACR)

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