循环肿瘤细胞（CTCs）由原发恶性肿瘤产生，作为遥远转移的“种子”。然而，CTCs如何逃避免疫监视仍然大多不为人知。在这里，我们单独分析了人胰腺导管腺癌CTCs、原发和转移病灶的转录组。细胞交互作用分析和体内外功能研究表明，CTCs和自然杀伤细胞（NK细胞）通过免疫检查点分子对HLA-E: CD94-NKG2A相互作用。通过阻断NKG2A或HLA-E表达的降低来破坏这种交互作用，增强了体外NK介导的肿瘤细胞杀伤，并防止了体内肿瘤的转移。机制研究表明，血小板源性RGS18通过AKT-GSK3β-CREB信号传导促进HLA-E的表达，在胰腺肿瘤肝转移过程中过表达RGS18。总之，血小板源性RGS18通过参与免疫检查点HLA-E: CD94-NKG2A保护CTCs免遭NK介导的免疫监视。中断抑制性信号可通过免疫清除CTCs来防止体内肿瘤转移。版权所有©2023 Elsevier Inc。保留所有权利。

Circulating tumor cells (CTCs), shed by primary malignancies, function as "seeds" for distant metastasis. However, it is still largely unknown how CTCs escape immune surveillance. Here, we characterize the transcriptomes of human pancreatic ductal adenocarcinoma CTCs, primary, and metastatic lesions at single-cell scale. Cell-interaction analysis and functional studies in vitro and in vivo reveal that CTCs and natural killer (NK) cells interact via the immune checkpoint molecule pair HLA-E:CD94-NKG2A. Disruption of this interaction by blockade of NKG2A or knockdown of HLA-E expression enhances NK-mediated tumor cell killing in vitro and prevents tumor metastasis in vivo. Mechanistic studies indicate that platelet-derived RGS18 promotes the expression of HLA-E through AKT-GSK3β-CREB signaling, and overexpression of RGS18 facilitates pancreatic tumor hepatic metastasis. In conclusion, platelet-derived RGS18 protects CTCs from NK-mediated immune surveillance by engaging the immune checkpoint HLA-E:CD94-NKG2A. Interruption of the suppressive signaling prevents tumor metastasis in vivo by immune elimination of CTCs.Copyright © 2023 Elsevier Inc. All rights reserved.