Diet-derived galactose reprograms hepatocytes to prevent T cell exhaustion and elicit antitumour immunity
Menée à l'aide de modèles murins, d'échantillons plasmatiques et d'échantillons tumoraux prélevés sur des patients atteints d'un cancer colorectal, d'un cancer du poumon ou d'un carcinome à cellules rénales, cette étude met en évidence un mécanisme par lequel le galactose, issu de l'alimentation, induit la production de protéines IGFBP-1 et stimule les lymphocytes T CD8+ via la modification du métabolisme des hépatocytes et l'inactivation du complexe protéique mTORC1
Dietary nutrients are inextricably linked to antitumour immune responses. However, the effect of diet-derived galactose on antitumour immunity remains unclear. Here we show that dietary galactose augments CD8+ T cell immunity to suppress tumour progression. High-galactose feeding drives hepatocyte-derived insulin-like growth factor binding protein 1 (IGFBP-1) production, thus restraining IGF-1 signalling-dependent T cell exhaustion. IGF-1 receptor (IGF-1R) deficiency in T cells potentiates antitumour CD8+ T cell responses and phenocopies high-galactose feeding by preventing T cell exhaustion. Circulating galactose reprograms hepatocyte metabolism to inactivate mTORC1, thereby inducing the production of IGFBP-1 to boost CD8+ T cell function. Furthermore, patients with cancer who have high plasma IGFBP-1 levels exhibit blocked T cell exhaustion and enhanced T cell responses in tumour tissues. These findings reveal that dietary galactose specifically elicits potent antitumour CD8+ T cell responses by facilitating hepatocyte-derived IGFBP-1 production, providing insights into the development of more effective immunotherapies against cancers.
Nature Cell Biology , résumé, 2025