Discovery of galectin-8 as an LILRB4 ligand driving M-MDSCs defines a class of antibodies to fight solid tumors

Abstract

LILRB4 is an immunosuppressive receptor, and its targeting drugs are undergoing multiple preclinical and clinical trials. Currently, the absence of a functional LILRB4 ligand in solid tumors not only limits the strategy of early antibody screening but also leads to the lack of companion diagnostic (CDx) criteria, which is critical to the objective response rate in early-stage clinical trials. Here, we show that galectin-8 (Gal-8) is a high-affinity functional ligand of LILRB4, and its ligation induces M-MDSC by activating STAT3 and inhibiting NF-κB. Significantly, Gal-8, but not APOE, can induce MDSC, and both ligands bind LILRB4 noncompetitively. Gal-8 expression promotes in vivo tumor growth in mice, and the knockout of LILRB4 attenuates tumor growth in this context. Antibodies capable of functionally blocking Gal-8 are able to suppress tumor growth in vivo. These results identify Gal-8 as an MDSC-driving ligand of LILRB4, and they redefine a class of antibodies for solid tumors.

Keywords: LILRB4; MDSC; cancer immunotherapy; galectin-8; immune checkpoint; immune evasion.