Yang Xing, Huang Ryan, Fang Meng, He Yubo, Xie Jingjing, Liu Xiaoye, Zhang Chengcheng, Lou Qi, Deng Mi, Xiong Wei, Lewis Cheryl, Sadek Zade, Gupta Ankit, Chen Lianqi, Zhang Xuewu, Guo Lei, Xu Lin, Zhang Ningyan, An Zhiqiang, Zhang Cheng Cheng
Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center, Houston, TX, USA.
Nat Immunol. 2025 Jul 24. doi: 10.1038/s41590-025-02233-4.
Immunosuppressive myeloid cells are important in a variety of physiological and pathological contexts, including tumor development, but how hormones might regulate their activity is unclear. Secretogranins, a family of secretory proteins in endocrine and neuronal cells, are proposed to function as prohormones or hormones, but their specific receptors are unknown. Here we show that secretogranin 2 (SCG2), a granin family member, functionally interacts with leukocyte immunoglobulin-like receptor B4 (LILRB4) on monocytic cells. Tumor-derived SCG2 promotes tumor growth in myeloid-specific LILRB4 transgenic mice in a T cell-dependent manner, whereas SCG2 deficiency in host mice impairs tumor progression and reduces infiltration of immunosuppressive monocytic cells. Blockade of LILRB4 abrogates SCG2-induced signaling, immunosuppression and tumor growth. Mechanistically, this SCG2-LILRB4 interaction triggers SHP recruitment and SHP-independent STAT3 activation. These findings define a function for SCG2 in regulating monocytic immunosuppression and suggest that the SCG2-LILRB4 axis might be a therapeutic target.
免疫抑制性髓系细胞在包括肿瘤发生在内的多种生理和病理环境中都很重要，但激素如何调节它们的活性尚不清楚。分泌粒蛋白是内分泌和神经元细胞中的一类分泌蛋白，被认为具有激素原或激素的功能，但其具体受体尚不清楚。在这里，我们表明分泌粒蛋白2（SCG2），一种颗粒蛋白家族成员，在单核细胞上与白细胞免疫球蛋白样受体B4（LILRB4）发生功能性相互作用。肿瘤来源的SCG2以T细胞依赖的方式促进髓系特异性LILRB4转基因小鼠的肿瘤生长，而宿主小鼠中SCG2的缺乏会损害肿瘤进展并减少免疫抑制性单核细胞的浸润。阻断LILRB4可消除SCG2诱导的信号传导、免疫抑制和肿瘤生长。从机制上讲，这种SCG2-LILRB4相互作用触发了SHP的募集和不依赖SHP的STAT3激活。这些发现确定了SCG2在调节单核细胞免疫抑制中的功能，并表明SCG2-LILRB4轴可能是一个治疗靶点。
