Contactin-4 suppresses antitumor T cell responses by engaging amyloid precursor protein.
Document Type
Article
Publication Date
10-11-2024
Original Citation
Jeon B,
Kim S,
Kim Y,
Yu H,
Park C,
Kim G,
Ha Y,
Kim G,
Kim H,
Palucka K,
Lee C,
Cha M,
Park H.
Contactin-4 suppresses antitumor T cell responses by engaging amyloid precursor protein. Sci Immunol. 2024;9(100):eadk7237.
Keywords
JGM, Animals, Mice, Humans, Amyloid beta-Protein Precursor, T-Lymphocytes, Mice, Inbred C57BL, Female, Cell Line, Tumor, Neoplasms, Male
JAX Source
Sci Immunol. 2024;9(100):eadk7237.
ISSN
2470-9468
PMID
39392894
DOI
https://doi.org/10.1126/sciimmunol.adk7237
Abstract
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.