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.

中文翻译：

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contactin-4 通过结合淀粉样蛋白前体蛋白抑制抗肿瘤 T 细胞反应


免疫检查点抑制剂具有大量先进的肿瘤治疗能力，但其有限的益处和仅在一部分患者中的强烈反应仍然具有挑战性。在这项研究中，我们探讨了 contactin-4 （CNTN4） 的免疫调节功能。CNTN4 在肿瘤组织中高表达，表达损害 T 细胞的抗肿瘤功能。CNTN4 与 T 细胞上的淀粉样蛋白前体蛋白 （APP） 结合，减弱了癌细胞和 T 细胞之间的结合，并减少了 T 细胞受体信号级联反应。我们开发了一种抗 CNTN4 抗体 （GENA-104A16） 和一种抗 APP 抗体 （5A7），可阻断 CNTN4 和 APP 之间的结合。GENA-104A16 或 5A7 的给药促进了同基因小鼠模型中的抗肿瘤 T 细胞反应，并增加了体内肿瘤浸润淋巴细胞。此外，CNTN4 水平升高与不良预后相关，与各种细胞毒性免疫相关标志物呈负相关。这些结果表明，CNTN4-APP 是 T 细胞中的抑制性检查点，代表了一种有前途的癌症免疫治疗策略。