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

• Published in: Science immunology 2024-10, Vol.9 (100), p.eadk7237
• Main Authors: Jeon, Bu-Nam, Kim, Sujeong, Kim, Yunjae, Yu, Hyunkyung, Park, Changho, Kim, Gihyeon, Ha, Youngeun, Kim, Gyeong-Yeon, Kim, Hyunuk, Palucka, Karolina A, Lee, Charles, Cha, Miyoung, Park, Hansoo
• Format: Article
• Language: English
• Subjects: Amyloid beta-Protein Precursor - immunology; Animals; Cell Line, Tumor; Female; Humans; Male; Mice; Mice, Inbred C57BL; Neoplasms - drug therapy; Neoplasms - immunology; T-Lymphocytes - immunology
• ISSN: 2470-9468; 2470-9468
• DOI: 10.1126/sciimmunol.adk7237

Immune checkpoint inhibitors have substantial advanced tumor treatment, but their limited benefits and strong responses in only a subset of patients remain challenging. In this study, we explored the immunomodulatory function of contactin-4 (CNTN4). CNTN4 was highly expressed in tumor tissues, and expression impaired the antitumor function of T cells. CNTN4 bound to amyloid precursor protein (APP) on T cells, which attenuated conjugation between cancer cells and T cells, and diminished T cell receptor signaling cascades. We developed an anti-CNTN4 antibody (GENA-104A16) and an anti-APP antibody (5A7) that blocked the binding between CNTN4 and APP. Administration of either GENA-104A16 or 5A7 promoted antitumor T cell responses in a syngeneic mouse model and increased tumor-infiltrating lymphocytes in vivo. Furthermore, elevated CNTN4 levels were associated with poor prognosis and negatively correlated with various cytotoxic immune-related markers. These results suggest that CNTN4-APP is an inhibitory checkpoint in T cells and represents a promising therapeutic strategy for cancer immunotherapy.