文章：

SLAMF6作为可靶向药物以抑制T细胞抗肿瘤免疫的因子

SLAMF6 as a drug-targetable suppressor of T cell immunity against cancer

原文发布日期：2026-02-11

DOI: 10.1038/s41586-026-10106-5

类型: Article

开放获取: 是

英文摘要：

Inhibitory receptors like PD-1 and CTLA-4 contribute to T cell dysfunction in cancer1,2,3. Monoclonal antibodies (mAbs) blocking the interactions in trans of these receptors with their ligands on cancer cells or in the tumour microenvironment lead to clinical responses in some but not all types of cancer. Signalling lymphocytic activation molecule 6 (SLAMF6, also known as Ly108) is a homotypic receptor preferentially expressed on progenitor or stem-like exhausted T (Tpex) cells, but not on terminally exhausted T (Tex) cells, as demonstrated in mouse models4,5,6,7,8,9. In contrast to Tex cells, Tpex cells retain the capacity for functional restoration after immune checkpoint blockade10,11,12. The role of SLAMF6 in T cells remains ambiguous, as it has both activating and inhibitory effects, complicating its evaluation as a therapeutic target. Here we find that SLAMF6 was triggered in cis by homotypic interactions at the T cell surface. These interactions elicited inhibitory effects that suppressed activation of T cells and limited anti-tumour immunity, independently of SLAMF6 expression on tumour cells. mAbs against human SLAMF6 with a robust ability to disrupt the cis interactions strongly augmented T cell activation, reduced the proportions of exhausted T cells and inhibited tumour growth in vivo. Collectively, these findings show that SLAMF6 functions exclusively as a T cell inhibitory receptor, which is triggered by cis homotypic interactions. They also position SLAMF6 as a promising target for therapies aimed at enhancing anti-tumour immunity, regardless of SLAMF6 expression on tumour cells.

摘要翻译： 

PD-1和CTLA-4等抑制性受体可导致癌症中T细胞功能失调¹⁻³。阻断这些受体与癌细胞或肿瘤微环境中配体发生反式相互作用的单克隆抗体，在部分（而非全部）癌症类型中能引发临床应答。淋巴细胞活化信号分子6（SLAMF6，亦称Ly108）是一种同型受体，在小鼠模型研究中证实其优先表达于祖细胞或干细胞样耗竭T细胞，而不表达于终末耗竭T细胞⁴⁻⁹。与终末耗竭T细胞不同，祖细胞耗竭T细胞在免疫检查点阻断后仍保留功能恢复能力¹⁰⁻¹²。SLAMF6在T细胞中的作用仍不明确——因其兼具激活与抑制效应，这使其作为治疗靶点的评估变得复杂。本研究发现SLAMF6可通过T细胞表面的同型相互作用发生顺式触发，这种相互作用引发抑制效应，从而抑制T细胞活化并限制抗肿瘤免疫，且该过程不依赖于肿瘤细胞上的SLAMF6表达。具有强力破坏顺式相互作用能力的人源SLAMF6单克隆抗体，能显著增强T细胞活化，减少耗竭T细胞比例，并在体内抑制肿瘤生长。综上，这些发现表明SLAMF6完全通过顺式同型相互作用触发，作为T细胞抑制性受体发挥作用。同时研究确立SLAMF6作为增强抗肿瘤免疫疗法的潜在靶点——无论肿瘤细胞是否表达SLAMF6。

原文链接：

SLAMF6 as a drug-targetable suppressor of T cell immunity against cancer