Myeloid reprogramming by poly(I:C) recruits progenitor-exhausted CD8+ T cells and sensitizes rhabdoid tumors to PD-1 blockade

Manriquez, V.; Cavada-Silva, S.; Beccaria, K.; Niborski, L. L.; Leruste, A.; Richer, W.; Vandenbogaert, M.; Han, Z.-Y.; Sedlik, C.; Denizeau, J.; Mesple, J.; Fusilier, Z.; Lesage L., L.; Goldstein, J.; Gerber-Ferder, Y.; Fitte-Duval, S.; Marziali, F.; Mena-Osuna, R.; Tosello-Boari, J.; Bouarich-Bourimi, R.; Pacini, M.-F.; Missolo-koussou, Y.; Bohec, M.; Baulande, S.; Benaroch, P.; Helft, J.; Moreau, H. D.; Waterfall, J. J.; Bourdeaut, F.; Piaggio, E.

doi:10.64898/2025.12.29.696858

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bioRxiv · 10.64898/2025.12.29.696858

Myeloid reprogramming by poly(I:C) recruits progenitor-exhausted CD8+ T cells and sensitizes rhabdoid tumors to PD-1 blockade

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Abstract

Immune exclusion remains a major barrier to effective immunotherapy in solid tumors. Given the abundance and plasticity of tumor-associated macrophages (TAMs) in many tumors, including pediatric tumors, we investigated whether TLR3 activation could reprogram them to facilitate immune access. Single-cell and spatial profiling in a mouse model of rhabdoid tumors showed that they are dominated by TLR3-expressing TAMs, whose depletion delays tumor growth. Treatment with the TLR3 agonist poly(I:C) promotes immune cell infiltration, including progenitor-exhausted CD8+ T cells, by multiple mechanisms including the reduction and reprogramming of immunosuppressive TAMs, promoting nitric-oxide production by peritumoral macrophages, and inducing CXCL9/10 production. Combined poly(I:C) and PD-1 blockade elicited durable, complete tumor rejection. Human macrophages from tumor biopsies showed conserved TLR3 responsiveness, underscoring translational potential. These findings uncover a mechanism by which TLR3-driven myeloid reprogramming transforms immune-excluded tumors into checkpoint-responsive ones, revealing a therapeutic path to overcome resistance to PD-1 blockade.

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Manriquez, V., Cavada-Silva, S., Beccaria, K., Niborski, L. L., Leruste, A., Richer, W., Vandenbogaert, M., Han, Z.-Y., Sedlik, C., Denizeau, J., Mesple, J., Fusilier, Z., Lesage L., L., Goldstein, J., Gerber-Ferder, Y., Fitte-Duval, S., Marziali, F., Mena-Osuna, R., Tosello-Boari, J., Bouarich-Bourimi, R., Pacini, M.-F., Missolo-koussou, Y., Bohec, M., Baulande, S., Benaroch, P., Helft, J., Moreau, H. D., Waterfall, J. J., Bourdeaut, F., Piaggio, E.. 2025-12-29. Myeloid reprogramming by poly(I:C) recruits progenitor-exhausted CD8+ T cells and sensitizes rhabdoid tumors to PD-1 blockade. https://doi.org/10.64898/2025.12.29.696858

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