Activation of the Siglec-7 inhibitory receptor: A novel approach for fighting cancer

Advanced systemic mastocytosis (SM) is a rare and still untreatable disease. Blocking antibodies against inhibitory receptors (IRs), also known as "immune checkpoints", have revolutionized anti-cancer treatment. IRs are expressed not only on normal immune cells, including mast cells (MCs) but also on neoplastic cells. Whether activation of IRs through monoclonal antibodies (mAbs) can lead to tumor growth inhibition remains mostly unknown. Here we show that the IR Siglec-7 is expressed by primary neoplastic MCs in patients with systemic mastocytosis and by MC leukemia (MCL) cell lines. Activation of Siglec-7 by anti-Siglec-7 mAb caused phosphorylation of Src homology region 2 domain-containing phosphatase-1 (SHP-1), reduced phosphorylation of KIT and of downstream signaling molecules, and induced growth inhibition in MCL cell lines. In SCID-beige mice injected with either the human MCL cell line HMC-1.1 and HMC-1.2 or with Siglec-7 transduced B cell lymphoma cells, anti-Siglec-7 mAb reduced tumor growth by a mechanism involving Siglec-7 cytoplasmic domains in “preventive” and “treatment” settings. Finally, we showed that anti-Siglec-7 affect also other cancer cells expressing Siglec-7, and reduces the cell growth of colon cancer carcinoma cell (LOVO) both in vitro and in-vivo. These data demonstrate that activation of Siglec-7 on MCL cell lines can inhibit their growth in vitro and in vivo. This might pave the way to additional treatment strategies for mastocytosis and also to other cancer type expressing Siglec-7 as well.