Sun Yunfan, Li Tong, Ding Lin, Wang Jiyan, Chen Chen, Liu Te, Liu Yu, Li Qian, Wang Chuyu, Huo Ran, Wang Hao, Tian Tongtong, Zhang Chunyan, Pan Baishen, Zhou Jian, Fan Jia, Yang Xinrong, Yang Wenjing, Wang Beili, Guo Wei
Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China.
Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, China.
Hepatology. 2025 Mar 1;81(3):791-807. doi: 10.1097/HEP.0000000000000934. Epub 2024 May 23.
Circulating tumor cells (CTCs) are precursors of cancer metastasis. However, how CTCs evade immunosurveillance during hematogenous dissemination remains unclear.
We identified CTC-platelet adhesions by single-cell RNA sequencing and multiplex immunofluorescence of blood samples from multiple cancer types. Clinically, CTC-platelet aggregates were associated with significantly shorter progression-free survival and overall survival in patients with HCC. In vitro, ex vivo, and in vivo assays demonstrated direct platelet adhesions gifted cancer cells with an evasive ability from NK cell killing by upregulating inhibitory checkpoint CD155 (PVR cell adhesion molecule), therefore facilitating distant metastasis. Mechanistically, CD155 was transcriptionally regulated by the FAK/JNK/c-Jun cascade in a platelet contact-dependent manner. Further competition assays and cytotoxicity experiments revealed that CD155 on CTCs inhibited NK-cell cytotoxicity only by engaging with immune receptor TIGIT, but not CD96 and DNAM1, another 2 receptors for CD155. Interrupting the CD155-TIGIT interactions with a TIGIT antibody restored NK-cell immunosurveillance on CTCs and markedly attenuated tumor metastasis.
Our results demonstrated CTC evasion from NK-cell-mediated innate immunosurveillance mainly through immune checkpoint CD155-TIGIT, potentially offering an immunotherapeutic strategy for eradicating CTCs.
循环肿瘤细胞（CTC）是癌症转移的前体。然而，CTC在血行播散过程中如何逃避免疫监视仍不清楚。
我们通过对多种癌症类型血液样本进行单细胞RNA测序和多重免疫荧光分析，确定了CTC与血小板的黏附情况。在临床上，CTC-血小板聚集体与肝癌患者显著缩短的无进展生存期和总生存期相关。在体外、离体和体内实验中均表明，直接的血小板黏附通过上调抑制性检查点CD155（PVR细胞黏附分子）赋予癌细胞逃避自然杀伤（NK）细胞杀伤的能力，从而促进远处转移。从机制上讲，CD155在血小板接触依赖的方式下由黏着斑激酶/应激活化蛋白激酶/ c-Jun级联反应进行转录调控。进一步的竞争实验和细胞毒性实验表明，CTC上的CD155仅通过与免疫受体TIGIT结合来抑制NK细胞的细胞毒性，而不与CD155的另外两个受体CD96和DNAX辅助分子1（DNAM1）结合。用TIGIT抗体阻断CD155-TIGIT相互作用可恢复NK细胞对CTC的免疫监视，并显著减弱肿瘤转移。
我们的结果表明，CTC主要通过免疫检查点CD155-TIGIT逃避NK细胞介导的天然免疫监视，这可能为根除CTC提供一种免疫治疗策略。
