加拿大蒙特利尔临床研究所André Veillette小组取得一项新突破。他们开发出了SLAMF6作为T细胞抗肿瘤免疫的药物靶向抑制因子。相关论文发表在2026年2月11日出版的《自然》杂志上。

在这里，研究人员发现SLAMF6是通过T细胞表面的同型相互作用顺式触发的。这些相互作用引起抑制作用，抑制T细胞的激活和限制抗肿瘤免疫，独立于肿瘤细胞上SLAMF6的表达。针对人SLAMF6的单克隆抗体具有破坏顺式相互作用的能力，可以增强T细胞的激活，降低衰竭T细胞的比例，并抑制肿瘤的体内生长。综上所述，这些发现表明SLAMF6仅作为T细胞抑制受体发挥作用，这是由顺式同型相互作用触发的。他们还将SLAMF6定位为旨在增强抗肿瘤免疫的治疗的有希望的靶点，无论SLAMF6在肿瘤细胞上的表达如何。

据了解，抑制性受体如PD-1和CTLA-4参与了癌症中的T细胞功能障碍。单克隆抗体（mAbs）阻断这些受体与它们的配体在癌细胞上或肿瘤微环境中的反式相互作用，导致一些但不是所有类型的癌症的临床反应。信号传导淋巴细胞激活分子6（SLAMF6，也称为Ly108）是一种同源型受体，优先表达在祖细胞或茎样衰竭T细胞（T_pex）上，而不表达在终末衰竭T细胞（T_ex）上，这在小鼠模型中得到了证明。与T_ex细胞相比，T_pex细胞在免疫检查点阻断后仍保留功能恢复能力。SLAMF6在T细胞中的作用仍然不明确，因为它具有激活和抑制作用，使其作为治疗靶点的评估变得复杂。

附：英文原文

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

Author: Li, Bin, Zhong, Ming-Chao, Galindo, Cristian Camilo, Dou, Jiayu, Qian, Jin, Tang, Zhenghai, Davidson, Dominique, Veillette, Andr

Issue&Volume: 2026-02-11

Abstract: 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.

DOI: 10.1038/s41586-026-10106-5

Source:https://www.nature.com/articles/s41586-026-10106-5