PA28γ-containing tumor-derived exosomes promote T-cell dysfunction in head and neck squamous cell carcinoma

Cancer cell-derived exosomes have been demonstrated to be effective as intercellular signal transmitters. PA28γ is known to be highly upregulated in cancers, but its specific role in the microenvironment remains unclear. Here, we demonstrated that PA28γ is loaded in exosomes released from head and neck squamous cell carcinoma (HNSCC) cells. Exosomal PA28γ is internalized by T cells, subsequently weakening their cytotoxic functions and increasing the expression of CD25 and LAG-3. Using a tumor orthotopic transplant model constructed with PA28γ^-/- mice, we found that T cells could take up PA28γ from tumor cells. Mass cytometry (CyTOF) analysis indicated that knockdown of PA28γ reduced the infiltration of CD25+ and LAG-3+ T cells. Importantly, high-PA28γ-expressing tumors are more responsive to CD25 and LAG-3 immune checkpoint therapy than low-PA28γ-expressing tumors in vivo. Mechanically, exosomal PA28γ enhanced T-cell exhaustion by degrading BCLAF1 after it was internalized. HNSCC cohort analysis revealed that the expression of PA28γ was positively correlated with the infiltration of CD25+ and LAG-3+ T cells and that high levels of these markers could predict a poor prognosis. In summary, exosomal PA28γ induces a T-cell exhaustion phenotype by inhibiting their tumor-killing ability, promoting malignant progression via the PA28γ/BCLAF1/CD25&LAG-3 pathway. These findings reveal a novel cell‒cell interaction between tumors and T cells in the HNSCC microenvironment.