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阻断PSGL-1诱导了人类瘤相关巨细胞的经典激活

Kevin Kauffman¹, Denise Manfra¹, Dominika Nowakowska¹

¹Verseau Therapeutics, Auburndale, Massachusetts.

Cancer research communications

|October 11, 2023

概括

阻断P-选择蛋白糖蛋白连接体-1 (PSGL-1) 重编程与瘤相关的巨细胞 (TAMs) 以减少免疫抑制. 这为患者提供了新的癌症治疗方法,这些患者对当前的免疫疗法有抗性,即使在T细胞贫乏的瘤中也是如此.

科学领域:

免疫学免疫学免疫学
在瘤学瘤学.
分子生物学分子生物学

背景情况:

瘤微环境,特别是抑制性瘤相关巨细胞 (TAMs),有助于固体癌症的耐药性.
在各种瘤类型中,P-选择因糖蛋白连接体-1 (PSGL-1) 在TAMs上高度表达,这表明它在免疫抑制中发挥作用.

研究的目的:

调查PSGL-1在维持TAMs免疫抑制状态中的作用.
探索PSGL-1封锁作为固体瘤的治疗策略,特别是在免疫疗法耐药的情况下.

主要方法:

对分子临床数据集的分析,以将细胞表面受体与TAM透相关联.
在体外和体内,siRNA介导的淘汰和抗体介导的PSGL-1抑制.
在合成基因小鼠模型和人性化瘤模型中评估瘤生长.
在患者衍生瘤培养物中评估细胞因子释放和T细胞激活标记物.

主要成果:

在多种瘤类型中证实了TAMs上的PSGL-1表达.
阻断或抑制PSGL-1导致巨细胞从巨细胞中释放出增强的促炎媒介.
单独或与PD-1阻断一起的PSGL-1阻断,在小鼠模型中降低了瘤生长.
用抗PSGL-1抗体治疗诱导了一种促炎性TAM开关,并在患者衍生培养物中增加IFNγ.

结论:

PSGL-1在维持TAMs的免疫抑制表型方面发挥着至关重要的作用.
PSGL-1封锁有效地将TAM重编程到促炎状态,增强抗瘤免疫力.
针对PSGL-1为对T细胞免疫疗法不反应或缺乏T细胞透的癌症提供了一个有希望的治疗策略.

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