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Cross-presentation of dead cell-associated antigens shapes the neoantigenic landscape of tumor immunity
Lim, K. H. J. Schulz, O. Lobon, I. Castro-Dopico, T. Zapata, L. Giampazolias, E. Frederico, B. Castellanos, C. A. Buck, M. D. Stainier, W.
Lim, K. H. J.
Schulz, O.
Lobon, I.
Castro-Dopico, T.
Zapata, L.
Giampazolias, E.
Frederico, B.
Castellanos, C. A.
Buck, M. D.
Stainier, W.
Abstract
Type 1 conventional dendritic cells (cDC1s) acquire and cross-present tumor antigens to prime CD8(+) T cells. Whether this selects for specific neoantigens is unclear. DNGR-1 (CLEC9A), a cDC1 receptor for F-actin exposed on dead cells, promotes cross-presentation of cell-associated antigens. Here we show that DNGR-1-deficient mice develop chemically induced tumors more rapidly and at higher incidence, and these are more frequently rejected on transplantation into wild-type recipients. Whole-exome sequencing reveals enrichment of predicted neoantigens derived from mutated F-actin-binding proteins. Consistent with this observation, tethering model antigens to F-actin enhances DNGR-1-dependent cross-presentation. These results suggest that DNGR-1-mediated recognition of F-actin exposed by dead cancer cells favors priming of CD8(+) T cells specific for cytoskeletal neoantigens, which can then drive immune escape of cancer cells lacking or reverting those mutations. Thus, neoantigen cross-presentation by cDC1 can determine the immune visibility of the tumor mutational landscape and sculpt cancer evolution by immunoediting.
Description
Date
2026
Publisher
Collections
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Article
Citation
Lim KHJ, Schulz O, Lobon I, Castro-Dopico T, Zapata L, Giampazolias E, et al. Cross-presentation of dead cell-associated antigens shapes the neoantigenic landscape of tumor immunity. Nature Immunology. 2026 JAN;27(1).