Small extracellular vesicles from the plasma of head and neck cancer patients induce dysfunctional T cell phenotypes.
TL;DR
The findings suggest that plasma sEVs contribute to systemic immune modulation in HNC by inducing dysfunctional T-cell phenotypes and underscores the need for further investigation into their relevance for immunotherapeutic strategies in HNC.
Abstract
Background
Head and neck cancer (HNC) is highly immunosuppressive. Despite advances with immune checkpoint (IC) inhibitors, many HNC patients fail to respond. Tumour-derived small extracellular vesicles (sEVs) may contribute to immune evasion and therapy resistance, possibly by altering T-cell phenotypes.
Method
Plasma sEVs were isolated from HNC patient samples and controls via size-exclusion chromatography. The plasma sEVs were characterised and analysed for their effects on CD4⁺ and CD8⁺ T-cell function, IC levels and gene expression.
Results
HNC patient-derived sEVs inhibit CD4+ and CD8+ T-cell function and promote CD8+ T-cell apoptosis, correlating with disease progression. Plasma sEVs can enhance the conversion of ATP to AMP and modulate the expression of ectonucleotidases. IC profiling revealed complex alterations, with CD4⁺ T cells showing increased TIGIT and CTLA-4 but decreased BTLA, PD-1, and LAG-3 expression, whereas CD8⁺ T cells showed a downregulation of both inhibitory and stimulatory ICs. PD-1 blockade did not completely prevent sEV-mediated T-cell suppression.
Conclusions
Our findings suggest that plasma sEVs contribute to systemic immune modulation in HNC by inducing dysfunctional T-cell phenotypes. The ability of plasma-derived sEVs to modulate IC expression on T cells underscores the need for further investigation into their relevance for immunotherapeutic strategies in HNC.