Clever-1 inhibition in human cancer: consequences and control of bexmarilimab-induced macrophage activation

Abstract

Cancer immunotherapy enhances the immune system’s ability to eliminate cancer cells for remarkable efficacy, but new therapies are needed to combat treatment resistance. Tumor-associated macrophages (TAMs) drive cancer progression largely through immunosuppression, and inhibiting their immunoregulatory scavenger receptor Clever-1 restores anti-tumor immunity in mice. A Clever-1-blocking humanized antibody bexmarilimab, developed to exploit this mechanism, entered first-in-human clinical testing for advanced solid tumors (MATINS trial) in 2018.

This thesis aimed to elucidate the immunological consequences of human macrophage Clever-1 blockade and to identify regulators of bexmarilimab treatment sensitivity. The presented transcriptomic, single-cell and spatially resolved analyses of clinical patient samples, patient-derived cells and tumor explants provide the first functional characterization of Clever-1 inhibition in human cancer.

We discovered bexmarilimab to disrupt tolerogenic lipid metabolism pathways and lysosomal acidification in monocytes and macrophages, resulting in their pro-inflammatory activation. In patients, monocyte and TAM reprogramming was accompanied by interferon and T-cell responses, both in the circulation and within tumors demonstrating disease stabilization. Similar immune responses occurred in one third of bexmarilimab-treated patient-derived cancer models, enabling recognition of bexmarilimab-sensitive tumor explant cultures with a gene signature identified in this thesis. Patient-derived cancer models additionally revealed that bexmarilimab-treated TAMs secrete CXCL10 for T-cell recruitment and that the tumor secretome regulates bexmarilimab responses more strongly than macrophage origin or cellular neighborhoods. Across the studies, bexmarilimab-induced immune responses were principally observed in interferon-poor tumor microenvironments, while chronic interferon priming impaired bexmarilimab-mediated macrophage activation. Additionally, responsive tumors had abundant intratumoral Clever-1+ TAMs and low PD-L1 expression, while lacking IL4I1+ TAMs and regulatory T cells. In conclusion, bexmarilimab activates macrophage- and T-cell-mediated immunity in non-inflamed tumors, which are mostly resistant to the current T-cell directed cancer immunotherapies effective in T-cell- and interferon-rich tumors.