Macrophages are immune cells present in all tissues where they participate to homeostatic processes. They are also present in malignant tumors where they favor cancer progression and the formation of metastases. The abundance of tumor-associated macrophages (TAMs) in a tumor is a factor of poor prognosis. Thus, controlling their infiltration in tumor tissue has a therapeutic potential. Véronique Le Cabec and co-workers have shown that it is possible to inhibit the migration of macrophages into tumors, leading to a decrease in tumor growth. This study is published in Cancer Immunology Research.
In a first step, the researchers identified the migration mode used in vivo by TAMs in a mouse fibrosarcoma model and in breast cancer explants, and showed that they use mesenchymal migration and utilize their own proteases to degrade the extracellular matrix of the tumor stroma. In inflamed dermis or in tissues surrounding malignant tumors, macrophages use the amoeboid migration mode that does not require proteolysis of the extracellular environment. In a second step, by treating mice with an inhibitor of metalloproteases (enzymes involved in the migration of TAMs), the researchers observed a reduced number of macrophages in tumors together with a decreased tumor growth (see Figure).In conclusion, macrophages use distinct migration modes in vivo. Targeting the mesenchymal mode used in tumors could be considered as a new strategy for cancer immunotherapy.
Mice developing fibrosarcoma are treated (or untreated: control) daily with a metalloprotease inhibitor that limits the mesenchymal migration of macrophages. The tumor growth is followed by fluorescence microscopy. A: images of two representative tumors at different days of treatment. B: Evolution of tumor size over time (6 mice in each group). C: Quantification of macrophages in the same tumors after 12 days of treatment.
This work was supported by INSERM Plan Cancer, Fondation pour la Recherche Médicale, Agence Nationale de la Recherche, Fondation Toulouse Cancer Santé, IPBS CNRS UMR5089, Ligue contre le cancer Région Midi-Pyrénées, Cancéropole Grand Sud-Ouest GSO-Emergence, Région Midi-Pyrénées, Fondation de France and the Université de Toulouse III.
The protease-dependent mesenchymal migration of tumor-associated macrophages as a target in cancer immunotherapy. Gui P, Ben-Neji M, Belozertseva E, Dalenc F, Franchet C, Gilhodes J, Labrousse A, Bellard E, Golzio M, Poincloux R, Maridonneau-Parini I, Le Cabec V. Cancer Immunol Res. 2018 Sep 4. pii: canimm.0746.2017. doi: 10.1158/2326-6066.cir-17-0746. [epub ahead of print] PMID: 30181209
CNRS scientist l Véronique Le Cabec
CNRS scientist l Isabelle Maridonneau-Parini