Macrophages from mice treated in vitro with the MACTIDE-V compound, which were exposed to breast cancer cells (in green) / Pablo Scodeller
Breast cancer is the most common cancer in women, and one of the deadliest forms is metastatic triple-negative breast cancer. This type affects the functioning of macrophages, key components of the immune system that, under normal conditions, help to eliminate pathogens, fight viruses, and promote wound healing. The tumour alters the activity of these cells, which form blood vessels around it and send signals that induce immunosuppression in T lymphocytes. In other words, they do not attack the tumour, allowing its spread.
Now, an international scientific team, led by the Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), in collaboration with the University of Tartu (Estonia), the Institute Oncology Veneto (Italy), the University of San Martín (Argentina), the Spanish National Center for Biotechnology (CNB-CSIC), and CIBER-BBN, has designed a chemical compound called MACTIDE-V, capable of reprogramming the activity of these macrophages and converting them into anti-tumoral agents to attack breast cancer.
The study, published in the prestigious journal Advanced Science, was carried out in vivo on female mice with metastatic triple-negative breast cancer, the most aggressive form of the disease. The results showed that MACTIDE-V increased the proportion of anti-tumour macrophages, reducing the tumour and even almost completely eliminating the metastasis produced.
“We decided to study this cancer, specifically triple-negative breast cancer, because there is currently no targeted treatment for it, due to the lack of specific receptors on cancer cells,” explains Pablo Scodeller, researcher at IQAC-CSIC and lead author of the study. The treatment for these tumours remains conventional chemotherapy, which has side effects and does not stimulate the immune system.
For the design of this chemical compound, the research team started with the structure of the peptide MACTIDE, a molecular sequence that binds to the CD206 receptor on the surface of macrophages. Collaboration with the Proteomics service at CNB-CSIC allowed them to combine it with the molecular structure of the drug Verteporfin, a medication used in ophthalmology. This combination resulted in the compound MACTIDE-V, which converted pro-tumoral macrophages into anti-tumoral ones.
Experiments on mouse models showed that the compound is capable of precisely targeting treatments to macrophages via intravenous administration, without accumulating in the liver. “This would allow us, in the future, to develop it into oral drugs for treatments,” says Scodeller.
They also tested the compound in combination with immunotherapies similar to Nivolumab or Pembrolizumab. “Although the tests combining MACTIDE-V with immunotherapy reduced both the tumour and metastasis, we observed that the treatment with MACTIDE-V alone was more effective than either immunotherapy alone, or the combination of both,” concludes Pablo Scodeller.
The research team has currently filed a patent application for the peptide design and its conjugation with the drug, and they will continue to study the compound in other types of cancers to better understand its mechanism of action.
A. Lepland, E. Peranzoni, U. Haljasorg, E. K. Asciutto, M. Crespí-Amer, L. Modesti, K. Kilk, M. Lombardia, G.Acosta, M. Royo, P. Peterson, I. Marigo, T. Teesalu, P. Scodeller. Peptide-Drug Conjugate for Therapeutic Reprogramming of Tumor-Associated Macrophages in Breast Cancer. Advanced Science. DOI: 10.1002/advs.202410288
IQAC-CSIC Communication
