27 okt. 2026
Schoenfeld J. et al. (BioRxiv)
Keywords
CD8+ T cells
Hepcidin
Iron
Pancreatic Ductal Adenocarcinoma
PR73
Tumor Infiltrating Lymphocytes
Main Findings
Pancreatic ductal adenocarcinoma (PDAC) is associated with very high rates of functional iron deficiency. Functional iron deficiency has previously been correlated with decreased CD8+ T cell function in vaccination and infection, but it is not clear how this could impact anti-tumor immunity. PDAC tumors are immunologically “cold”, limiting the efficacy of immune checkpoint blockade or other T cell-based therapies. As a higher frequency of TILs is associated with better outcomes, the authors aimed to investigate the relationship between functional iron deficiency and CD8+ T cell infiltration of PDAC tumors. Leveraging clinical outcomes from thousands of patients, the authors established a negative correlation between pre-treatment iron deficiency and patient survival. Patients recently diagnosed with PDAC were prospectively monitored for iron deficiency and hepcidin levels. It was determined that higher serum hepcidin was associated with worse survival and fewer tumor infiltrating lymphocytes. Mouse models of PDAC did not recapitulate this increase in hepcidin, so the authors used PR73, a hepcidin mimetic, to induce hypoferremia. This resulted in immunologically “cold” tumors which more closely mimicked the human disease. To test iron restriction in vivo, the authors created a novel system using iron regulatory proteins (IRP) 1 and 2 which would either activate or inhibit mCherry expression based on iron sensing. They found that TIL and exhausted cells were the most iron restricted. This iron restriction most negatively impacted T cells exposed to high doses of antigen.
Limitations & Suggestions
While the authors have done a lot of work on the impact of hepcidin-based iron restriction on TILs, they have not addressed the source of increased hepcidin during PDAC. While hepcidin is primarily produced by hepatocytes, it has also been shown to be produced by some cancer cells. Whether this is IL-6-dependent in humans is unclear. Thus, it would be valuable to assess if the PDAC cancer cells also secrete hepcidin, which could explain some of the increased metabolic pressure on the TILs independent of antigen restimulation.
Patients are defined for analyses as either “high” or “low” for serum hepcidin, where “high” hepcidin is associated with reduced overall survival. How these cutoffs were defined is not clear, as hepcidin levels can fluctuate widely and there appears to be a large overlap in range across patients.
Iron depletion impacted the intratumoral T cells, but not the peripheral T cells which is a bit surprising. The mechanism by which this selectivity occurred was not fully elucidated. The authors could make this work more robust by testing whether these differences were due to increased antigen stimulation in the tumor microenvironment, or if hepcidin differentially impacts iron in the tumor versus the peripheral environment.
Many patients with PDAC have peripheral insulin resistance and impaired insulin secretion. Because insulin upregulates the transcription of hepcidin in hepatocytes, this makes the cellular source and original cause of high hepcidin levels in these patients more intriguing. Are these patients taking insulin and if so, how could that confound their serum hepcidin levels?
Significance/Novelty
While the link between PDAC and functional iron deficiency has previously been established, this is the first time that hepcidin has been correlated with decreased patient outcomes in PDAC. This study employed large patient datasets to establish a novel correlation between hepcidin and tumor lymphocyte infiltration. The authors defined a novel susceptibility of highly stimulated cells to iron restriction through hepcidin. They improved murine models of PDAC to better recapitulate human disease using PR73 to induce hypoferremia. Lastly, the authors created a novel IRP IRE binding reporter which may be useful in future in vivo studies of iron regulation beyond cancer.
Credit
Reviewed by Meredith Crockett and Kelsey Voss as part of a cross-institutional journal club between the Max-Delbrück Center Berlin, the University of Virginia, the Medical University of Vienna and other life science institutes in Vienna.
The author declares no conflict of interests in relation to their involvement in the review.