{"_":"CTSL缺失通过抑制外周CD8 T细胞的抗肿瘤功能，导致肺癌对anti-PD-1免疫治疗耐药。","sup":["+"]}

摘要(中文译文)

非小细胞肺癌（NSCLC）发病率高，且多数患者会对anti-PD-1免疫治疗产生耐药，导致生存期缩短。现有证据表明，外周T细胞，尤其是CD8 T细胞，在anti-PD-1免疫治疗应答中发挥关键作用。然而，损害外周CD8 T细胞功能并由此驱动anti-PD-1免疫治疗耐药的关键分子仍不清楚。本研究旨在证明外周CD8 T细胞中组织蛋白酶L（CTSL）表达缺失是驱动NSCLC anti-PD-1治疗耐药的关键因素。我们采用流式细胞术追踪接受anti-PD-1治疗的NSCLC患者外周CD8 T细胞中CTSL的动态表达模式，以及其在不同T细胞亚群中的纵向分布。随后，我们研究了外周CD8 T细胞中CTSL表达水平与抗肿瘤效应分子表达之间的关联。最后，通过生物信息学分析、流式细胞术、ELISA和药理学干预，我们探索了CTSL与NLRP3炎症小体活化在介导CD8 T细胞抗肿瘤功能中的功能关系。外周CD8 T细胞中CTSL表达被证明是NSCLC患者对anti-PD-1免疫治疗获得更佳临床应答的预测因素（）。亚群分析显示，在anti-PD-1耐药患者中，效应记忆CD8 T细胞和终末分化效应记忆CD8 T细胞中CTSL表达显著降低。在机制上，CTSL上调增强了CD8 T细胞中功能分子的表达，包括穿孔素、颗粒酶、IFN-γ和Ki67。功能探索实验进一步表明，外周CD8 T细胞中CTSL与NLRP3表达不仅呈正相关，而且NLRP3的激活可逆转CTSL抑制所诱导的CD8 T细胞抗肿瘤功能障碍。外周CD8 T细胞中CTSL表达缺失是驱动NSCLC anti-PD-1免疫治疗耐药的关键因素。CTSL缺失可能通过抑制NLRP3炎症小体活化损害CD8 T细胞的抗肿瘤功能。本研究不仅为预测anti-PD-1治疗应答提供了潜在的循环生物标志物，也为理解耐药机制提供了新视角。

Abstract

Non-small cell lung cancer (NSCLC) has a high incidence rate, and most patients develop resistance to anti-PD-1 immunotherapy, resulting in shortened survival. Current evidence suggests that peripheral T cells, particularly CD8 T cells, play a key role in the response to anti-PD-1 immunotherapy. However, the key molecules that impair peripheral CD8 T cell function and thereby drive resistance to anti-PD-1 immunotherapy remain unclear. This study aims to demonstrate that loss of cathepsin L (CTSL) expression in peripheral CD8 T cells is a critical factor driving resistance to anti-PD-1 therapy in NSCLC. Using flow cytometry, we tracked the dynamic expression patterns of CTSL in peripheral CD8 T cells from NSCLC patients receiving anti-PD-1 therapy, as well as its longitudinal distribution across different T cell subsets. We then investigated the association between CTSL expression levels in peripheral CD8 T cells and the expression of anti-tumor effector molecules. Finally, through bioinformatics analysis, flow cytometry, ELISA, and pharmacological interventions, we explored the functional relationship between CTSL and NLRP3 inflammasome activation in mediating the anti-tumor function of CD8 T cells. CTSL expression in peripheral CD8 T cells was demonstrated as a predictor of improved clinical response to anti-PD-1 immunotherapy in NSCLC (). Subset analysis revealed that in anti-PD-1-resistant patients, CTSL expression was significantly reduced in effector memory CD8 T cells and terminally differentiated effector memory CD8 T cells. Mechanistically, CTSL upregulation enhanced the expression of functional molecules in CD8 T cells, including perforin, granzyme, IFN-γ, and Ki67. Functional exploration experiments further showed not only a positive correlation between CTSL and NLRP3 expression in peripheral CD8 T cells, but also that activation of NLRP3 reversed the anti-tumor dysfunction of CD8 T cells induced by CTSL inhibition. Loss of CTSL expression in peripheral CD8 T cells is a key factor driving resistance to anti-PD-1 immunotherapy in NSCLC. CTSL loss may impair the anti-tumor function of CD8 T cells by inhibiting NLRP3 inflammasome activation. This study not only provides a potential circulating biomarker for predicting response to anti-PD-1 therapy, but also offers new perspectives for understanding the mechanisms of resistance.

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