Contactin-4 suppresses antitumor T cell responses by engaging amyloid precursor protein

Area of Science:

• Immunology
• Cancer Biology
• Molecular Medicine

Background:

• Immune checkpoint inhibitors (ICIs) show promise in cancer treatment but benefit only a subset of patients.
• Identifying novel immune checkpoints is crucial for improving immunotherapy efficacy.
• The immunomodulatory role of contactin-4 (CNTN4) in cancer immunity is largely unexplored.

Purpose of the Study:

• To investigate the function of contactin-4 (CNTN4) in modulating anti-tumor immune responses.
• To determine the potential of targeting the CNTN4-amyloid precursor protein (APP) axis for cancer immunotherapy.

Main Methods:

• Analyzed CNTN4 expression in tumor tissues.
• Investigated the interaction between CNTN4 and APP on T cells.
• Developed and tested anti-CNTN4 and anti-APP antibodies in a syngeneic mouse model.
• Correlated CNTN4 levels with patient prognosis and immune markers.

Main Results:

• CNTN4 expression was high in tumor tissues and impaired T cell anti-tumor function.
• CNTN4 binds to APP on T cells, inhibiting cancer cell-T cell conjugation and T cell receptor signaling.
• Anti-CNTN4 (GENA-104A16) and anti-APP (5A7) antibodies promoted T cell responses and increased tumor-infiltrating lymphocytes in vivo.
• Elevated CNTN4 levels correlated with poor prognosis and reduced cytotoxic immune markers.

Conclusions:

• The CNTN4-APP pathway acts as an inhibitory immune checkpoint on T cells.
• Targeting CNTN4 or APP represents a promising therapeutic strategy for enhancing cancer immunotherapy.