Caught in the Act: Tumor-Immune Interactions in Circulation of Patients with Immune Marker Positive Circulating Tumor Cells

Liquid biopsy enables the study of cancer through blood samples by examining circulating tumor cells (CTCs) and large extracellular vesicles (LEVs). A subset of CTCs expressing immune markers has been reported, but the basis for this phenotype has remained unclear. In this study, we analyzed patient blood samples using high-resolution immunofluorescence imaging to investigate how tumor cells and vesicles may acquire these immune features. We observed direct physical interactions between white blood cells (WBCs) and the CTCs or LEVs that expressed immune markers, and such interactions occurred exclusively in patients who harbored these immune-marker-positive CTCs. In many instances, WBCs partially enveloped the tumor cells or vesicles, and immune markers were specifically concentrated at the regions of contact. Proteomic analysis identified CD4+ T cells as the predominant interacting immune cell type and confirmed that the same immune markers present on these WBCs were also found on the interacting CTCs and LEVs. These results support membrane transfer during cell-to-cell contact as a plausible mechanism for the acquisition of immune markers and provide in vivo evidence of contact-dependent tumor-immune interactions in circulation.

Naghdloo A, Kamal M, Tessone D, Hennes V, Hicks J, Kuhn P. Caught in the Act: Tumor-Immune Interactions in Circulation of Patients with Immune Marker Positive Circulating Tumor Cells. Cancers. 2025; 17(22):3667. https://doi.org/10.3390/cancers17223667