Antibody-induced TREM2 ectodomain shedding inhibits TREM2 signaling in macrophage

Antibody-based therapy targeting triggering receptor expressed on myeloid cells 2 (TREM2) is a promising tumor immunotherapy strategy that blocks the TREM2 signaling pathway. How to develop inhibitory antibodies with better performance is the current challenge. Here, we aimed to explore how TREM2's stalk region (136-172 aa) protects the ectodomain from shedding and develop antibodies to promote TREM2 shedding and inhibit signal activation. Molecular dynamics simulations indicated a self-folding conformation in the stalk region of TREM2. The TREM2 risk variant (H157Y) reduces the stability of this conformation by affecting hydrogen bond formation. Histidine 154 (H154) also participated in maintaining the stability of the self-folding conformation and preventing shedding of TREM2. The screened antibody test-2 could target stalk region of TREM2, induce the shedding of TREM2 and regulate the expression of inflammatory factors in THP1 cells. These results suggest that antibodies targeting the stalk region of TREM2 have the potential to serve as inhibitory antibodies.