Abstract 492: CNTN4 is a novel immune checkpoint protein that inhibits proliferation of T cell by interacting with APP

Abstract

Contactin 4 (CNTN4, alias BIG-2) is a glycosylphosphatidylinositol (GPI)-anchored neuronal membrane protein that functions as cell adhesion, playing a key role in maintaining the mechanical integrity and signaling properties of the synapse. However, its function and crosstalk with immune cells have not been investigated. Therefore, we tried to find out what role CNTN4 plays in cell adhesion between T cells and antigen-presenting cells (APC). CNTN4 has several binding partners such as the amyloid precursor protein (APP), amyloid-like protein 1 (APLP1), and protein tyrosine phosphatase receptor γ (PTPRγ). In previous papers, the APP was reported to be expressed in T cells. We investigated whether CNTN4 can bind to T cells. The degree of binding of CNTN4 to T cells varied depending on the expression level of APP, and that the binding between these two proteins was in the form of trans-binding. And it was confirmed that the direct binding is achieved through fibronectin 1~2 domain of CNTN4 and KPI (Kunitz protease inhibitor) domain of APP. Furthermore, we investigated whether CNTN4 has any effect on T cell proliferation. T cell proliferation and cytokine secretion assays by using CNTN4 recombinant protein showed that CNTN4 significantly inhibits proliferation and cytokine secretion (IL-2, IFN-γ, TNF-α) of T cells more than PD-L1. Although the expression of CNTN4 in immune cells has not yet been clearly confirmed, the expression of CNTN4 in various carcinomas have confirmed by using western, IHC, and bioinformatic data analysis. In particular, the higher the expression of CNTN4 in tumor tissues of gastric cancer patients, the worse the prognosis is in the survival curve. Our findings suggest that CNTN4 may behave as an immune checkpoint protein similar to other B7 family members. Further investigation of the CNTN4 signaling pathway and its receptors are warranted by our data and may lead to novel therapeutic interventions. Citation Format: Mi Young Cha, Bu-Nam Jeon, Areum Jeong, Joo-Yeon Chung, Hyunsuk Yang, Kyung Mi Park, Hansoo Park. CNTN4 is a novel immune checkpoint protein that inhibits proliferation of T cell by interacting with APP [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 492.