Scholten David, El-Shennawy Lamiaa, Jia Yuzhi, Zhang Youbin, Hyun Elizabeth, Reduzzi Carolina, Hoffmann Andrew D, Almubarak Hannah F, Tong Fangjia, Dashzeveg Nurmaa K, Sun Yuanfei, Squires Joshua R, Lu Janice, Platanias Leonidas C, Wasserfall Clive H, Gradishar William J, Cristofanilli Massimo, Fang Deyu, Liu Huiping
Department of Pharmacology.
Driskill Graduate Program in Life Sciences.
J Clin Invest. 2025 Sep 16;135(18). doi: 10.1172/JCI193521.
The immune ecosystem is central to maintaining effective defensive responses. However, it remains largely understudied how immune cells in the peripheral blood interact with circulating tumor cells (CTCs) in metastasis. Here, blood analysis of patients with advanced breast cancer revealed that over 75% of CTC-positive blood specimens contained heterotypic CTC clusters with CD45+ white blood cells (WBCs), which correlates with breast cancer subtypes, racial groups, and decreased survival. CTC-WBC clusters included overrepresented T cells and underrepresented neutrophils. Specifically, a rare subset of CD4 and CD8 double-positive T (DPT) cells was 140-fold enriched in CTC clusters versus their frequency in WBCs. DPT cells shared properties with CD4+ and CD8+ T cells but exhibited unique features of T cell exhaustion and immune suppression. Mechanistically, the integrin heterodimer α4β1, also named very late antigen 4 (VLA-4), in DPT cells and its ligand, VCAM1, in tumor cells are essential mediators of DPT-CTC clusters. Neoadjuvant administration of anti-VLA-4 neutralizing antibodies markedly blocked CTC-DPT clusters, inhibited metastasis, and extended mouse survival. These findings highlight a pivotal role of rare DPT cells in fostering cancer dissemination through CTC clustering. It lays a foundation for developing innovative biomarker-guided therapeutic strategies to prevent and target cancer metastasis.
免疫生态系统对于维持有效的防御反应至关重要。然而，外周血中的免疫细胞如何与转移过程中的循环肿瘤细胞（CTC）相互作用，在很大程度上仍未得到充分研究。在这里，对晚期乳腺癌患者的血液分析显示，超过75%的CTC阳性血液样本中含有与CD45+白细胞（WBC）形成的异型CTC簇，这与乳腺癌亚型、种族群体以及生存率降低相关。CTC-WBC簇中T细胞占比过高，而中性粒细胞占比过低。具体而言，一种罕见的CD4和CD8双阳性T（DPT）细胞亚群在CTC簇中的富集程度比在WBC中的频率高140倍。DPT细胞兼具CD4+和CD8+T细胞的特性，但表现出T细胞耗竭和免疫抑制的独特特征。从机制上讲，DPT细胞中的整合素异二聚体α4β1，也称为极迟抗原4（VLA-4），及其在肿瘤细胞中的配体VCAM1，是DPT-CTC簇的关键介质。新辅助给予抗VLA-4中和抗体可显著阻断CTC-DPT簇，抑制转移，并延长小鼠生存期。这些发现突出了罕见的DPT细胞在通过CTC聚集促进癌症播散中的关键作用。这为开发创新的生物标志物导向治疗策略以预防和靶向癌症转移奠定了基础。
