T cells are critical mediators of antitumor immunity and a major target for cancer immunotherapy. Antibody blockade of inhibitory receptors such as PD-1 can partially restore the activity of tumor-infiltrating lymphocytes (TILs). However, the activation signals required to promote TIL responses are less well characterized. Here we show that the antitumor activity of CD8 and γδ TIL is supported by interactions between junctional adhesion molecule–like protein (JAML) on T cells and its ligand coxsackie and adenovirus receptor (CXADR) within tumor tissue. Loss of JAML through knockout in mice resulted in accelerated tumor growth that was associated with an impaired γδ TIL response and increased CD8 TIL dysfunction. In mouse tumor models, therapeutic treatment with an agonistic anti-JAML antibody inhibited tumor growth, improved γδ TIL activation, decreased markers of CD8 TIL dysfunction, and significantly improved response to anti–PD-1 checkpoint blockade. Thus, JAML represents a novel therapeutic target to enhance both CD8 and γδ TIL immunity.

中文翻译：

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JAML 促进 CD8 和 γδ T 细胞抗肿瘤免疫，是癌症免疫治疗的新靶点

T细胞是抗肿瘤免疫的关键介质，也是癌症免疫治疗的主要靶点。PD-1等抑制性受体的抗体阻断可以部分恢复肿瘤浸润淋巴细胞（TILs）的活性。然而，促进 TIL 反应所需的激活信号的特征不太清楚。在这里，我们表明 CD8 和 γδ TIL 的抗肿瘤活性受到 T 细胞上的连接粘附分子样蛋白 (JAML) 与其配体柯萨奇和肿瘤组织内的腺病毒受体 (CXADR) 之间的相互作用的支持。在小鼠中通过敲除导致 JAML 的丧失导致肿瘤生长加速，这与 γδ TIL 反应受损和 CD8 TIL 功能障碍增加有关。在小鼠肿瘤模型中，使用激动性抗 JAML 抗体进行治疗可抑制肿瘤生长，改善 γδ TIL 活化，减少 CD8 TIL 功能障碍的标志物，并显着改善对抗 PD-1 检查点阻断的反应。因此，JAML 代表了一种新的治疗靶点，可增强 CD8 和 γδ TIL 免疫。