Iron-boost for the body's defense against cancer

Teams from the Medical Faculty of Heidelberg University, the European Molecular Biology Laboratory (EMBL) Heidelberg, the German Cancer Research Center (DKFZ), and Leiden University have shown in mice that certain immune cells keep lung tumors in check if they have previously been treated with iron nanoparticles. The recently published work was funded by the Translational Lung Research Center Heidelberg, a partner of the German Center for Lung Research.

Certain immune cells, known as macrophages, are attracted to tumors and can attack them - or protect them from other immune cells and chemotherapy. Introducing iron particles can reliably steer the macrophage behavior towards cancer defense. This discovery was made by a team led by Professor Martina Muckenthaler, Medical Faculty Heidelberg, University of Heidelberg, and group leader at the Molecular Medicine Partnership Unit (MMPU), a cooperation between the Medical Faculty Heidelberg and EMBL Heidelberg. The scientists investigated a form of non-small cell lung carcinoma that initially responds well to targeted drugs, but becomes resistant over time and grows back. In mice suffering from this type of lung cancer, specially prepared iron nanoparticles were able to slow tumor regrowth, as the team recently reported in the journal ACS Nano. How long this effect lasts and whether it is transferrable to humans cannot yet be determined from these results. Nevertheless, the team believes that this novel immunotherapy has the potential to enhance the effects of current therapies.

The research was conducted in collaboration with the groups of Prof. Dr. Rocio Sotillo, Director of the Division of Molecular Basis of Thoracic Tumors at DKFZ, Prof. Dr. Matthias W. Hentze, Director of EMBL, and Prof. Dr. Matthias Barz, Director of the Department of BioTherapeutics at the Leiden Academic Centre for Drug Research (LACDR), University of Leiden, Netherlands. The lead authors are former doctoral students Natalie K. Horvat, MMPU, and Sara Chocarro, DKFZ.

Iron makes macrophages aggressive

The idea of an iron booster for immune cells came from observations in a completely different disease affecting the blood: When deformed red blood cells are broken down in hereditary sickle cell anemia, the iron contained within them enters the blood and tissues. "When macrophages in the liver absorb this iron, they attack surrounding liver cells and cause tissue damage," says Professor Muckenthaler, who investigates various disorders of iron metabolism at the Center for Translational Biomedical Iron Metabolism Research at Heidelberg University Hospital. "As red blood cells are also broken down in the tumor environment, we took a closer look at the tumor microenvironment."

Lung tumors stimulate the growth of blood vessels in their surroundings in order to be better supplied with oxygen and nutrients. From these blood vessels, red blood cells enter the often inflamed tissue and are broken down by macrophages. Their iron accumulates in the macrophages. In tissue samples from patients with non-small cell lung carcinoma (NSCLC), the team previously found that if such an "iron curtain" is present around the tumor, the tumors remain smaller and patients have a better prognosis than those without iron accumulation. "The macrophages in the vicinity of the tumors are more aggressive against cancer. We wanted to take advantage of this natural activation of cancer defense," the scientist explains.

The team administered specially prepared iron nanoparticles from Professor Barz's laboratory to mice suffering from a subtype of human lung tumors, so-called ALK-positive NSCLCs, via the respiratory tract. The animals had initially been treated with the common tumor drug crizotinib, which precisely targets an altered protein of this type of cancer and temporarily suppresses the tumors completely. "Targeted drugs such as Crizotinib are a major advance in the treatment of this specific type of cancer. Unfortunately, the tumors become resistant after an average of 19 months. If we were able to additionally activate the immune system with the iron booster, we could potentially gain disease- and symptom-free time for patients,” says cooperation partner Professor Sotillo.

Also suitable for other tumors?

When macrophages took up the iron nanoparticles, they released substances that harmed the cancer cells and attracted further immune cells. After treatment with crizotinib, the tumors grew back at a significantly slower rate over the two-week trial period. There were no side effects. "These results do not yet say anything about whether and for how long lung cancer patients would benefit from such treatment. But they show a promising approach that we would also like to test in other forms of lung cancer as well as liver tumors and breast cancer,” says Muckenthaler.

Non-small cell lung cancer (NSCLC) accounts for about 80 percent of all lung tumors. The subtype of ALK-positive non-small cell lung cancer, affecting about 5 percent of NSCLC patients, is characterized by a specific genetic alteration (EML4-ALK fusion oncogene). Patients with this cancer type usually have never or rarely smoked. The usual treatment consists of treatment with targeted inhibitors such as Crizotinib. However, these tumors respond poorly to common immunotherapies.

Source: Press release Heidelberg University Hospital

Original publication: Horvat NK, Chocarro S, Marques O, et al. Superparamagnetic Iron Oxide Nanoparticles Reprogram the Tumor Microenvironment and Reduce Lung Cancer Regrowth after Crizotinib Treatment. ACS Nano. 2024;18(17):11025-11041. doi: 10.1021/acsnano.3c08335