Rare Subset of T Cells Form Heterotypic Clusters with Circulating Tumor Cells to Foster Cancer Metastasis

Area of Science:

• Immunology and Cancer Biology
• Tumor Microenvironment and Metastasis
• Cellular Interactions in Cancer

Background:

• The interaction between immune cells and circulating tumor cells (CTCs) is crucial for understanding cancer metastasis but remains understudied.
• Immune cells in peripheral blood may play a significant role in the dissemination of cancer cells.
• Identifying these interactions can reveal new therapeutic targets for preventing metastasis.

Purpose of the Study:

• To investigate the interaction between immune cells and CTCs in patients with advanced breast cancer.
• To characterize the immune cells involved in CTC clusters and their role in metastasis.
• To explore potential therapeutic strategies targeting these interactions.

Main Methods:

• Analysis of blood specimens from 1,529 advanced breast cancer patients.
• Flow cytometry, ImageStream, and single-cell RNA sequencing to analyze CTC-white blood cell (WBC) clusters.
• Preclinical mouse models using anti-VLA4 neutralizing antibodies to assess therapeutic efficacy.

Main Results:

• Over 75% of CTC-positive samples showed heterotypic clusters of CTCs with WBCs, correlating with specific breast cancer subtypes and decreased survival.
• A rare subset of CD4 and CD8 double-positive T (DPT) cells, exhibiting immune-suppressive features, were highly enriched in CTC clusters.
• The integrin VLA4 on DPT cells and VCAM1 on tumor cells were identified as key mediators of cluster formation; anti-VLA4 therapy inhibited metastasis in vivo.

Conclusions:

• Immune-suppressive DPT cells play a pivotal role in fostering cancer dissemination by clustering with CTCs.
• Targeting the VLA4-VCAM1 interaction offers a promising strategy to block CTC-immune cell clustering and inhibit metastasis.
• These findings provide a foundation for developing novel biomarkers and therapeutics to combat cancer metastasis.