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

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.

Type 1 interferons and Foxo1 down-regulation play a key role in age-related T-cell exhaustion in mice.

Foxo family transcription factors are critically involved in multiple processes, such as metabolism, quiescence, cell survival and cell differentiation. Although continuous, high activity of Foxo transcription factors extends the life span of some species, the involvement of Foxo proteins in mammalian aging remains to be determined. Here, we show that Foxo1 is down-regulated with age in mouse T cells. This down-regulation of Foxo1 in T cells may contribute to the disruption of naive T-cell homeostasis with age, leading to an increase in the number of memory T cells. Foxo1 down-regulation is also associated with the up-regulation of co-inhibitory receptors by memory T cells and exhaustion in aged mice. Using adoptive transfer experiments, we show that the age-dependent down-regulation of Foxo1 in T cells is mediated by T-cell-extrinsic cues, including type 1 interferons. Taken together, our data suggest that type 1 interferon-induced Foxo1 down-regulation is likely to contribute significantly to T-cell dysfunction in aged mice.