Blocking Clever-1 on human monocytes inhibits the growth of aggressive breast cancer

Abstract

Immunosuppressive tumor microenvironment limits antitumoral immunity and facilitates cancer progression. Tumor-associated macrophages that are mainly derived from blood monocytes, are central regulators of the tumor immune microenvironment and appealing targets in cancer immunotherapy. A subset of monocytes and macrophages express a scavenger and adhesion receptor Clever-1 that on tumor-associated macrophages promotes immunosuppression, cancer growth and metastasis. Nevertheless, the role of monocyte Clever-1 in cancer is largely unknown. The aim of this thesis was to determine how inhibition of monocyte Clever-1 with a humanized anti-Clever-1 antibody, FP-1305, affects the growth of cancer cells. This was investigated in monocyte-cancer cell co-culture that was followed with live-imaging. Additionally, the binding of FP-1305 on macrophage Clever-1 and the effect of FP-1305 treatment on monocyte function were investigated. Our results show that Clever-1+ monocytes induce the growth of triple-negative breast cancer cells in monocyte co-culture, while treating the monocytes with FP-1305 prevents the co-culture growth. Interestingly, Clever-1+ monocytes did not promote the growth of less aggressive luminal A breast cancer cells. In addition, FP-1305 treatment did not affect the viability of monocytes nor did it affect cancer cell proliferation directly. Immunofluorescence stainings revealed that FP-1305 epitope was more accessible at the adhering surface of macrophages, suggesting that FP-1305 binds to the active form of Clever-1. In conclusion, anti-Clever-1 treatment of human monocytes can suppress the growth of aggressive breast cancer without having undesirable effects on monocyte function. This further supports our previous findings that Clever-1 is an attractive cancer immunotherapy target.