PO.IM02.06 · 免疫学
PRTN3 通过蛋白水解切割 CXCL9 抑制 KRAS 突变型肺腺癌中细胞毒性免疫细胞的活化及抗肿瘤免疫
PRTN3 suppresses cytotoxic immune-cell activation and antitumoral immunity through proteolytic cleavage of CXCL9 in KRAS mutant lung adenocarcinoma
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
KRAS 突变型肺腺癌（LUAD）对免疫检查点阻断（ICB）在很大程度上无应答。在此，我们定义了一种由肿瘤分泌的蛋白酶 3（PRTN3）介导的 KRAS 突变型 LUAD 中的新型免疫逃逸机制，PRTN3 通过蛋白水解使 T 细胞趋化因子 CXCL9 失活，从而形成免疫“冷”微环境。在机制上，KRAS 信号通过 c-Myc 在转录水平上上调 PRTN3。分泌的 PRTN3 随后在肿瘤微环境中切割并使 CXCL9 失活，从而破坏 CXCL9/CXCR3 信号，抑制细胞毒性 NK 细胞和 CD8+ T 细胞的招募与活化。在 LUAD 患者中，高 PRTN3 表达与低 CXCL9 活性相关。关键在于，PRTN3 的基因敲除与抗 PD-1 治疗协同作用，在体内恢复抗肿瘤免疫。此外，应用一种抗水解的 CXCL9 变体足以显著增强 LUAD 患者来源类器官中 T 细胞介导的杀伤作用，确立了靶向该轴的治疗潜力。我们的研究结果确立了肿瘤来源的 PRTN3 作为免疫抑制的关键介导因子，以及 KRAS 驱动的 LUAD 中一个有前景的治疗靶点。
查看英文原文 English abstract
KRAS-mutant lung adenocarcinoma (LUAD) is largely refractory to immune-checkpoint blockade (ICB). Here, we define a novel immune evasion mechanism in KRAS-mutant LUAD mediated by tumor-secreted protease 3 (PRTN3), which proteolytically inactivates the T-cell chemoattractant CXCL9 to create an immune-cold microenvironment. Mechanistically, KRAS signaling transcriptionally upregulates PRTN3 via c-Myc. Secreted PRTN3 then cleaves and inactivates CXCL9 in the tumor microenvironment, thereby disrupting CXCL9/CXCR3 signaling and suppressing the recruitment and activation of cytotoxic NK and CD8+ T cells. In LUAD patients, high PRTN3 expression is associated with low CXCL9 activity. Crucially, genetic ablation of PRTN3 synergizes with anti-PD-1 therapy to restore antitumor immunity in vivo. Moreover, the application of a hydrolysis-resistant CXCL9 variant is sufficient to potently enhance T-cell-mediated killing in LUAD patient-derived organoids, establishing the therapeutic potential of targeting this axis. Our findings establish tumor-derived PRTN3 as a key mediator of immune suppression and a promising therapeutic target in KRAS-driven LUAD.
利益披露 Disclosure
R. Xiang, None..
Y. Liu, None.