Dual PD-L1/TIGIT blockade induces PNAd+ HEV-like vessels and CD62L+ lymphocyte recruitment, driving rhabdoid tumor rejection

Fitte-Duval, S.; Silva, S. C.; Mena-Osuna, R.; Hoare, O.; Niborski, L. L.; Denizeau, J.; Lesage, L.; Richer, W.; Sedlik, C.; Beccaria, K.; Veryssiere, M.; Bouarich-Bourimi, R.; Goldstein, J.; Marziali, F.; Boari, J. T.; Masliah-Planchon, J.; Han, Z.-Y.; Rocha, D.; Bohec, M.; Baulande, S.; Waterfall, J. J.; Manriquez, V.; Bourdeaut, F.; Piaggio, E.

doi:10.64898/2025.12.15.692132

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bioRxiv · 10.64898/2025.12.15.692132

Dual PD-L1/TIGIT blockade induces PNAd+ HEV-like vessels and CD62L+ lymphocyte recruitment, driving rhabdoid tumor rejection

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Abstract

Rhabdoid tumors (RTs) are aggressive pediatric malignancies with poor prognosis and limited immunotherapy options. Here, we investigate the therapeutic potential of combined PD-L1 (Programmed cell death ligand 1) and TIGIT (T cell immunoreceptor with Ig and ITIM domains) immune checkpoint blockade in RTs using a preclinical murine model that recapitulates key features of human ATRT (Atypical teratoid rhabdoid tumors) subtypes. Transcriptomic analyses of human and murine RTs reveal co-expression of TIGIT and PD-1 (Programmed cell death 1) pathway components and their ligands, particularly in immune-infiltrated subtypes, supporting a rationale for dual blockade. Combination therapy induces complete tumor regression, prolongs survival, and reprograms the tumor immune microenvironment by enriching CD62L naive and central memory T cells and promoting selective T-cell clonal expansion. Notably, dual blockade initiates PNAd (Peripheral node addressin) high endothelial venule (HEV)-like structures, associated with focal lymphocyte clustering and enhanced immune cell recruitment. These findings reveal a mechanistic link between vascular remodeling and immune infiltration and support dual TIGIT and PD-L1 inhibition as a promising immunotherapeutic strategy for RTs.

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Fitte-Duval, S., Silva, S. C., Mena-Osuna, R., Hoare, O., Niborski, L. L., Denizeau, J., Lesage, L., Richer, W., Sedlik, C., Beccaria, K., Veryssiere, M., Bouarich-Bourimi, R., Goldstein, J., Marziali, F., Boari, J. T., Masliah-Planchon, J., Han, Z.-Y., Rocha, D., Bohec, M., Baulande, S., Waterfall, J. J., Manriquez, V., Bourdeaut, F., Piaggio, E.. 2025-12-17. Dual PD-L1/TIGIT blockade induces PNAd+ HEV-like vessels and CD62L+ lymphocyte recruitment, driving rhabdoid tumor rejection. https://doi.org/10.64898/2025.12.15.692132

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