Twenty-year persistence of WT1-specific cytotoxic T lymphocytes in peritumoral brain tissue by peptide vaccine therapy: Transcriptomic evidence for resident memory T-cell induction.

BACKGROUND

Sustained immune surveillance at tumor sites is considered essential for effective cancer immunotherapy; however, direct evidence of immune surveillance in humans is limited due to difficulty obtaining tumor and peritumoral tissues through invasive procedures.

METHODS

Peritumoral brain tissue was obtained during reoperation from a patient with diffuse astrocytoma who had received continuous Wilms' tumor gene 1 (WT1) peptide vaccination for 20 years. WT1 tetramer-positive CD8+ T cells were analyzed by flow cytometry, followed by T-cell receptor repertoire analysis and single-cell RNA sequencing.

RESULTS

A high level of T-cell infiltration was observed in peritumoral brain tissue, despite the immune-privileged nature of the central nervous system. Notably, 38.4% of CD8+  T cells were WT1-tetramer positive, exhibiting an oligoclonal pattern similar to that observed in peripheral blood. Single-cell RNA sequencing demonstrated that WT1-specific cytotoxic T lymphocytes (CTLs) were predominantly composed of resident memory T cells (Trm) and terminally differentiated effector memory T cells (TEMRA), along with a small fraction of cycling T cells. Interestingly, Trm-like subsets were also detected among WT1-specific CTLs in peripheral blood.

CONCLUSION

These findings provide in situ evidence of long-term persistence of WT1-specific CTLs in the human brain by continuous WT1 peptide vaccination. Such local immune surveillance may have contributed to the prevention of relapse in this patient. Single-cell RNA sequencing suggests that long-lived Trm may contribute to the persistence of immune surveillance through self-renewal and generation of cytotoxic TEMRA. This study offers insights into long-term anti-tumor immunity and may inform future optimization of cancer vaccine therapy.