肿瘤细胞治疗研究
英文原题：Dual blockade of PD-1 and NKG2A prevents NK cell senescence and reprograms the immunosuppressive microenvironment in pancreatic cancer.
免疫检查点阻断 (ICB) 在胰腺导管腺癌 (PDAC) 中疗效有限。
免疫检查点阻断（ICB）治疗胰腺导管腺癌（PDAC）的疗效有限。本研究表明，ICB诱导的IFN-γ信号可上调胰腺肿瘤细胞上的H2-T23；H2-T23与NK细胞上的NKG2A相互作用后，通过激活p38 MAPK及STAT1/3通路诱导NK细胞衰老，损害NK细胞细胞毒性并限制抗肿瘤免疫。联合阻断PD-1和NKG2A可有效预防NK细胞衰老、恢复其功能并增强抗肿瘤免疫。从机制上看，联合治疗促进NK细胞来源的CCL5，并以NK细胞依赖方式促进CD8⁺ T细胞募集，从而同时激活先天和适应性免疫。对9种癌症单细胞测序数据的分析进一步发现，免疫治疗后NK细胞衰老增加，提示这可能是跨癌种的共同机制。本研究确定NK细胞衰老是免疫治疗耐药的关键机制，并支持将PD-1和NKG2A双重靶向作为PDAC有前景的治疗策略。
Immune checkpoint blockade (ICB) shows limited efficacy in pancreatic ductal adenocarcinoma (PDAC). Here, we demonstrate that ICB-induced IFN- signaling upregulates H2-T23 on pancreatic tumor cells, which interacts with NKG2A on NK cells to induce NK cell senescence through activation of p38 MAPK and STAT1/3 pathways. This impairs NK cell cytotoxicity and restricts antitumor immunity. Dual blockade of PD-1 and NKG2A effectively prevents NK cell senescence, restores NK cell function, and enhances antitumor immunity. Mechanistically, the combination therapy promotes NK cell-derived CCL5 and facilitates CD8 + T cell recruitment in an NK cell-dependent manner, thereby activating both innate and adaptive immunity. Analysis of single-cell sequencing data across nine cancer types further revealed increased NK cell senescence after immunotherapy, suggesting a potentially common pan-cancer mechanism. These findings identify NK cell senescence as a key mechanism underlying immunotherapy resistance and support dual targeting of PD-1 and NKG2A as a promising therapeutic strategy for PDAC.
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