Small EV in plasma of triple negative breast cancer patients induce intrinsic apoptosis in activated T cells

Small extracellular vesicles (sEV) in TNBC patients’ plasma promote T cell dysfunction and tumor progression. Researchers at the University of Pittsburgh School of Medicine show that tumor cell-derived exosomes (TEX) carrying surface PDL-1, PD-1, Fas, FasL, TRAIL, CTLA-4 and TGF-β1 induce apoptosis of CD8+T and CD4+T cells but spare B and NK cells. Inhibitors blocking TEX-induce receptor/ligand signals and TEX pretreatments with proteinase K or heat fail to prevent T cell apoptosis. Cytochalasin D, Dynosore or Pit Stop 2, partly inhibit TEX uptake but do not prevent T cell apoptosis. TEX entry into T cells induces cytochrome C and Smac release from mitochondria and caspase-3 and PARP cleavage in the cytosol. Expression of survival proteins is reduced in T cells undergoing apoptosis. Independently of external death receptor signaling, TEX entry into T cells induces mitochondrial stress, initiating relentless intrinsic apoptosis, which is responsible for death of activated T cells in the tumor-bearing hosts. The abundance of TEX in cancer plasma represents a danger for adoptively transferred T cells, limiting their therapeutic potential.

Immunoregulatory proteins expressed on the surface of recipient immune cells and on TEX or sEV of malignant and non-malignant origins

Fig. 4

a The heatmap presenting mean RFI values for proteins expressed on the surface of activated primary CD4 + T, CD8 + T, B and NK cells. b The heatmap presenting mean RFI values for proteins found on the surface of TEX1, TEX2, HaCaT sEV, TNBC Pt-sEV and HD-sEV. c An image of a T cell interacting with various TEX (shown as blue vesicles) that carry immunoregulatory proteins on the surface membrane. TEX binding to complementary receptors expressed by the T cell initiate immunoregulatory signals which result in immune downregulation [(-)Ireg] and/or immune stimulation. The sum of these simultaneously delivered signals will determine whether TEX mediate immune suppression or immune stimulation in a recipient T cell. Note that a single sEV might carry multiple signaling proteins on its surface membrane.

Mondal SK, Haas D, Han J et al. (2023) Small EV in plasma of triple negative breast cancer patients induce intrinsic apoptosis in activated T cells. Commun Biol [Epub ahead of print]. [article]

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