Systemic iron sequestration restricts the intratumoral CD8+ T cell landscape in pancreas cancer
Schoenfeld, J.; Noel, J.; McGinnis, C.; Fu, C.; Alagesan, B.; Hernandez, E.; Jee, J.; Schultz, N.; Morris, Q.; Lowe, S.; Cloonan, S.; Connolly, J.; Chaligne, R.; Kelsen, D.; Yu, K.; Zhang, W.; OReilly, E.; Satpathy, A.; Ganz, T.; Vardhana, S.
Show abstract
Systemic iron sequestration occurs frequently in cancer due to inflammation-driven expression of the iron-regulatory hormone hepcidin. The impact of systemic iron availability on tumoral immunity is unclear. Here, we show that elevated serum hepcidin is associated with reduced survival and decreased intratumoral CD8+ T cells in patients with pancreas cancer. While hepcidin is not induced in murine tumor models, administration of a hepcidin mimetic phenocopies the T-cell-depleted tumor microenvironment seen in patients. Mechanistically, chronic antigen-driven mitochondrial dysfunction disrupts iron metabolism and selectively depletes high avidity CD8+ T cells during iron restriction. These findings establish a direct link between hepcidin-mediated iron sequestration and tumoral immunity and nominate systemic iron dysregulation as a therapeutic target to enhance anti-tumoral CD8+ T cell responses.
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