肿瘤细胞治疗研究
英文原题：High Mobility Group Protein B1 Decreases Surface Localization of PD-1 to Augment T-cell Activation.
高迁移率族蛋白 B1 (HMGB1) 是一种危险信号分子，已被发现可触发有效的抗肿瘤免疫应答。
高迁移率族蛋白B1（HMGB1）是一种危险信号分子，已知可诱发有效的抗肿瘤免疫应答，但其抗肿瘤作用机制尚未完全明确。本研究发现，非小细胞肺癌患者化疗诱导的HMGB1释放与CD8阳性T细胞上的PD-1表达呈负相关。体外分析显示，HMGB1处理可显著降低CD8阳性T细胞PD-1表达。进一步分析表明，HMGB1通过诱导动力蛋白介导的PD-1内化，使其早期进入细胞质中的内吞囊泡，随后在溶酶体中降解，从而降低PD-1表达。在异种移植模型中，存在HMGB1时，靶向HER2的嵌合抗原受体（CAR）T细胞功能增强。这些数据揭示HMGB1可作为肺癌PD-1信号的负向调节因子；其对CAR-T细胞的抗肿瘤作用也可能为新的联合免疫治疗提供理论依据。
High-mobility group protein B1 (HMGB1) is a danger signaling molecule that has been found to trigger an effective antitumor immune response. However, the mechanisms underlying its antitumor effects are not fully understood. Here, we found that HMGB1 release induced by chemotherapy in patients with non-small cell lung cancer was negatively correlated with PD-1 expression on CD8+ T cells. In vitro analysis indicated that treatment with HMGB1 led to a significant decrease in the level of expression of PD-1 on CD8+ T cells. Further analysis demonstrated that HMGB1 reduced PD-1 expression by inducing dynamin-mediated internalization of the protein, leading to early endocytosis in the cytoplasm, and subsequently degradation in the lysosomes. In a xenograft model, HER2-targeted chimeric antigen receptor (CAR) T cells had enhanced function in the presence of HMGB1. These data identify a role for HMGB1 as a negative regulator of PD-1 signaling in lung cancer and the observed antitumor effect of HMGB1 on CAR T cells may provide a theoretical foundation for a new immunotherapy combination.
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