Small Extracellular Vesicles Reduce Anti-Tumor T-Cell Responses in CLL Progression

By Cecilia Brown - Last Updated: October 24, 2022

A new study suggests small extracellular vesicles secreted by leukemia cells reduce anti-tumor T-cell responses during chronic lymphocytic leukemia (CLL) progression.

Ernesto Gargiulo, PhD, of the Luxembourg Institute of Health and colleagues used mouse models of CLL to study cancer-microenvironment interactions. It was important to use a mouse model to evaluate small extracellular vesicle communication in the tumor microenvironment, as it “has been modeled mainly in cell culture” and the relevance of this communication in “cancer pathogenesis and progression in vivo is less characterized,” Dr. Gargiulo and colleagues wrote.

The small extracellular vesicles isolated directly from CLL tissue were enriched in specific microRNAs and immune checkpoint ligands. The “distinct molecular components” of tumor-derived small extracellular vesicles altered the transcriptome, proteome, and metabolome in CD8-postive T-cells, according to Dr. Gargiulo and colleagues. These alterations caused decreased function and led to cell exhaustion ex vivo and in vivo.

The researchers defined the specific cargo-mediated alterations on CD8-positive T-cells by using antagomirs and blocking antibodies. They used a Rab27a/b knockout to abrogate small extracellular vesicle biogenesis, which “dramatically delayed” CLL pathogenesis, according to the researchers. The delayed pathogenesis phenotype did not occur in the knockout if the researchers introduced exogenous leukemic small extracellular vesicles or depleted CD8-positive T-cells.

Expression of small extracellular vesicle-related genes is correlated with “poor outcomes” in patients with CLL, which suggests that small extracellular vesicle profiling may be a prognostic tool, Dr. Gargiulo and colleagues concluded.

Reference

Gargiulo E, Viry E, Morande PE, et al. Extracellular vesicle secretion by leukemia cells in vivo promotes CLL progression by hampering antitumor T-cell responses. Blood Cancer Discov. 2022. doi:10.1158/2643-3230.BCD-22-0029

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