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Serial Changes of Circulating Tumor Cells in Patients with Hepatocellular Carcinoma Treated with Atezolizumab Plus Bevacizumab

ABSTRACT: Background and aims: Immune checkpoint inhibitors have promising outcomes in patients with hepatocellular carcinoma (HCC); however, there is no reliable biomarker for predicting disease progression. Circulating tumor cells (CTCs) derived from peripheral blood have attracted attention in monitoring therapeutic efficacy. In this study, CTCs were serially collected from patients with HCC undergoing atezolizumab plus bevacizumab (Atezo+Bev) treatment, and changes in molecular expression and CTC numbers were analyzed to identify effective biomarkers. Approach and results: The peripheral blood samples were collected serially from 22 patients with HCC treated with Atezo+Bev, and CTCs were enriched using RosetteSep. The CD45(-)PanCK(+) cell counts were measured using flow cytometry. RNA extracted from enriched CTCs underwent targeted RNA sequencing with next-generation sequencing (NGS) and performed unsupervised hierarchical clustering analysis. Changes in CTC numbers during Atezo+Bev treatment reflected the tumor volume. NGS analysis revealed that patients with elevated transforming growth factor (TGF)-β signaling molecules had a poorer response, whereas those with elevated apoptosis signaling molecules had a favorable response (p < 0.05). In addition, compared with changes in CTC counts, changes in TGF-β signaling molecule expression in CTCs accurately and promptly predicted treatment response. Conclusions: NGS analysis of CTC-derived RNA showed that changes in TGF-β signaling molecules predict treatment response earlier than changes in CTC counts. These findings suggest that changes in the expression of TGF-β molecules in CTCs could serve as novel biomarkers for the early prediction of therapeutic response in patients with unresectable HCC undergoing Atezo+Bev therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE261186 | GEO | 2024/07/17

REPOSITORIES: GEO

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Project description:Cancer cells metastasize through the bloodstream either as single migratory circulating tumor cells (CTCs) or as multicellular groupings (CTC-clusters). Existing technologies for CTC enrichment are designed primarily to isolate single CTCs, and while CTC-clusters are detectable in some cases, their true prevalence and significance remain to be determined. Here, we developed a microchip technology (Cluster-Chip) specifically designed to capture CTC-clusters independent of tumor-specific markers from unprocessed blood. CTC-clusters are isolated through specialized bifurcating traps under low shear-stress conditions that preserve their integrity and even two-cell clusters are captured efficiently. Highly parallel architecture of the chip allows deterministic screening of clinically relevant volumes of blood samples at slow, and hence, non-damaging flow rates. Using the Cluster-Chip, we identify CTC-clusters in 30-40% of patients with metastatic cancers of the breast, prostate and melanoma. RNA sequencing of CTC-clusters confirms their tumor origin and identifies leukocytes within the clusters as being tissue-derived macrophages. Together, the development of a device for efficient capture of CTC-clusters will enable detailed characterization of their biological properties and role in cancer metastasis. We used the Cluster-Chip to capture CTC-clusters from the blood of a breast cancer patient with high CTC counts, released CTC-clusters in solution, stained them with TexasRed-conjugated antibodies against the leukocyte cell surface markers CD45, CD14 and CD16, and then isolated intact CTC-clusters individually using a micromanipulator. From a single time point, we retrieved 15 CTC-clusters, and each of those clusters was individually subjected to RNA-sequencing analysis using a next generation platform (SOLiD 5500). In addition, two leukocytes were isolated from the blood of a healthy donor were individually subjected to RNA-sequencing analysis using the same platform.

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Serial Changes of Circulating Tumor Cells in Patients with Hepatocellular Carcinoma Treated with Atezolizumab Plus Bevacizumab

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