The Protease-Dependent Mesenchymal Migration of Tumor-Associated Macrophages as a Target in Cancer Immunotherapy

Macrophage recruitment is essential for tissue homeostasis but detrimental in most cancers. Tumor-associated macrophages (TAMs) play a key role in cancer progression. Controlling their migration is, thus, potentially therapeutic. It is assumed that macrophages use amoeboid motility in vivo like other leukocytes. However, it has not yet been explored. We examined TAM migration using intravital microscopy in mouse tumors and by monitoring ex vivo tissue infiltration in human surgical samples. We demonstrated that TAMs perform protease-dependent and ROCK-independent mesenchymal migration inside mouse fibrosarcoma and breast cancer explants using their own matrix metalloproteases (MMP). In contrast, macrophages use ROCK-dependent and protease-independent amoeboid migration inside inflamed ear derma and in connective tissue at the tumor periphery. We also showed that inhibition of mesenchymal migration correlates with decreased TAM recruitment and tumor growth. In conclusion, this study elucidates how macrophages migrate in vivo, and it reveals that the MMP-dependent migration mode of TAMs provides a rationale for a new strategy in cancer immunotherapy: to target TAMs specifically through their motility. Cancer Immunol Res; 6(11); 1337–51. ©2018 AACR.

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