Immune checkpoint blockade is a promising approach to activate antitumor immunity and improve the survival of patients with cancer. V-domain immunoglobulin suppressor of T cell activation (VISTA) is an immune checkpoint target; however, the downstream signaling mechanisms are elusive. Here, we identify leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) as a VISTA binding partner, which acts as an inhibitory receptor by engaging VISTA and suppressing T cell receptor signaling pathways. Mice with T cell–specific LRIG1 deletion developed superior antitumor responses because of expansion of tumor-specific cytotoxic T lymphocytes (CTLs) with increased effector function and survival. Sustained tumor control was associated with a reduction of quiescent CTLs (TCF1⁺ CD62L^hi PD-1^low) and a reciprocal increase in progenitor and memory-like CTLs (TCF1⁺ PD-1⁺). In patients with melanoma, elevated LRIG1 expression on tumor-infiltrating CD8⁺ CTLs correlated with resistance to immunotherapies. These results delineate the role of LRIG1 as an inhibitory immune checkpoint receptor and propose a rationale for targeting the VISTA/LRIG1 axis for cancer immunotherapy.

中文翻译：

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LRIG1 与配体 VISTA 结合并损害肿瘤特异性 CD8+ T 细胞反应


免疫检查点阻断是激活抗肿瘤免疫并提高癌症患者生存率的一种有前途的方法。 V 域 T 细胞激活免疫球蛋白抑制因子 (VISTA) 是免疫检查点靶点；然而，下游信号传导机制却难以捉摸。在这里，我们将富含亮氨酸的重复序列和免疫球蛋白样结构域 1 (LRIG1) 确定为 VISTA 结合伴侣，它通过参与 VISTA 并抑制 T 细胞受体信号通路来充当抑制性受体。 T 细胞特异性 LRIG1 缺失的小鼠由于肿瘤特异性细胞毒性 T 淋巴细胞 (CTL) 的扩增以及效应功能和存活率的增加而产生了优异的抗肿瘤反应。持续的肿瘤控制与静态 CTL (TCF1 ⁺ CD62L ^hi PD-1 ^low ) 的减少以及祖细胞和记忆样 CTL 的相互增加有关（TCF1 ⁺ PD-1 ⁺ ）。在黑色素瘤患者中，肿瘤浸润性 CD8 ⁺ CTL 上 LRIG1 表达升高与免疫治疗耐药相关。这些结果描绘了 LRIG1 作为抑制性免疫检查点受体的作用，并提出了针对癌症免疫治疗的 VISTA/LRIG1 轴的基本原理。