Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing, P.R. China.
Department of Immunology, School of Basic Medical Sciences, Binzhou Medical University, Yantai, Shandong, 264003, P.R. China.
Cell Death Dis. 2023 Oct 16;14(10):684. doi: 10.1038/s41419-023-06199-9.
Leukocyte-associated immunoglobulin-like receptor-1 (LAIR1), an immune receptor containing immunoreceptor tyrosine-based inhibiory motifs (ITIMs), has emerged as an attractive target for cancer therapy. However, the intrinsic function of LAIR1 in gliomas remains unclear. In this study, the poor prognosis of glioma patients and the malignant proliferation of glioma cells in vitro and in vivo were found to be closely correlated with LAIR1. LAIR1 facilitates focal adhesion kinase (FAK) nuclear localization, resulting in increased transcription of cyclin D1 and chemokines/cytokines (CCL5, TGFβ2, and IL33). LAIR1 specifically supports in the immunosuppressive glioma microenvironment via CCL5-mediated microglia/macrophage polarization. SHP2 (PTP domain mutant) or FAK (non-nuclear localizing mutant) significantly reversed the LAIR1-induced growth enhancement in glioma cells. In addition, LAIR1 (ITIMs mutant) and SHP2 mutants significantly reduced FAK nuclear localization, as well as CCL5 and cyclin D1 expression. Further experiments revealed that the ITIMs of LAIR1 recruited SH2-containing phosphatase 2 (SHP2), which then interacted with FAK and induced FAK nuclear localization. This study uncovered a critical role for intrinsic LAIR1 in facilitating glioma malignant progression and demonstrated a requirement for LAIR1 and SHP2 to enhance FAK nuclear localization.
白细胞相关免疫球蛋白样受体 1（LAIR1）是一种含有免疫受体酪氨酸抑制基序（ITIM）的免疫受体，已成为癌症治疗的一个有吸引力的靶点。然而，LAIR1 在神经胶质瘤中的内在功能仍不清楚。本研究发现，神经胶质瘤患者的预后不良以及神经胶质瘤细胞在体外和体内的恶性增殖与 LAIR1 密切相关。LAIR1 促进粘着斑激酶（FAK）核定位，导致细胞周期蛋白 D1 和趋化因子/细胞因子（CCL5、TGFβ2 和 IL33）转录增加。LAIR1 通过 CCL5 介导的小胶质细胞/巨噬细胞极化，特异性支持免疫抑制性神经胶质瘤微环境。SHP2（PTP 结构域突变体）或 FAK（非核定位突变体）显著逆转了 LAIR1 诱导的神经胶质瘤细胞生长增强。此外，LAIR1（ITIM 突变体）和 SHP2 突变体显著降低了 FAK 的核定位以及 CCL5 和细胞周期蛋白 D1 的表达。进一步的实验表明，LAIR1 的 ITIM 募集了含 SH2 结构域的磷酸酶 2（SHP2），然后与 FAK 相互作用并诱导 FAK 核定位。本研究揭示了内在的 LAIR1 在促进神经胶质瘤恶性进展中的关键作用，并证明了 LAIR1 和 SHP2 增强 FAK 核定位的必要性。
