CNTN4/APP axis of cancer cells and T-cells

Abstract

Abstract Immune checkpoint inhibitors have significantly advanced tumor treatment, but their limited benefits and strong responses in only a subset of patients persist as challenges. CNTN4, a neuronal membrane protein involved in cell adhesion and synapse signaling, has unclear immunomodulatory functions. In this study, we reveal the immune checkpoint role of CNTN4 in T-cell proliferation and activation both in vitro and in vivo. We found that CNTN4, highly expressed in numerous tumor tissues, impedes T-cell proliferation, cytotoxicity, and the secretion of cytotoxic cytokines in vitro. On T cells, CNTN4 binds to two APP isoforms, APP770 and APP751, which results in attenuated TCR signaling and diminished cell adhesion capacity. To target this interaction, we developed GENA-104A16 against CNTN4 and an anti-APP antibody (5A7) that blocks the binding between CNTN4 and APP. Administering these two antibodies demonstrated anti-tumor effects in a syngeneic tumor mouse model and increased tumor-infiltrating lymphocytes within tumor tissues in vivo. Furthermore, elevated CNTN4 levels are associated with poor prognosis and negatively correlated with various cytotoxic immune-related markers. In conclusion, CNTN4 serves as a bona fide immune checkpoint protein and represents a promising therapeutic target for developing immunotherapeutic drugs.