Myeloid reprogramming by poly(I:C) recruits progenitor-exhausted CD8+ T cells and sensitizes rhabdoid tumors to PD-1 blockade
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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V., M., S., C., K., B., L., N. L., A., L., W., R., M., V., Z.-Y., H., C., S., J., D., J., M., Z., F., L., L. L., J., G., Y., G., S., F., F., M., R., M., J., T., R., B., M.-F., P., Y., M., M., B., S., B., P., B., J., H., D., M. H., J., W. J., F., B., E., P. (2025). Myeloid reprogramming by poly(I:C) recruits progenitor-exhausted CD8+ T cells and sensitizes rhabdoid tumors to PD-1 blockade. arXiv preprint arXiv:10.64898/2025.12.29.696858.
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., and Piaggio, E.. "Myeloid reprogramming by poly(I:C) recruits progenitor-exhausted CD8+ T cells and sensitizes rhabdoid tumors to PD-1 blockade." arXiv preprint arXiv:10.64898/2025.12.29.696858 (2025).