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The aged tumor microenvironment limits T cell control of cancer.

Alex C Y ChenSneha JaiswalDaniela MartinezCansu YerindeKeely JiVelita MirandaMegan E FungSarah A WeissMaria ZschummelKazuhiro TaguchiChristopher S GarrisThorsten R MempelNir HacohenDebattama R Sen
Published in: Nature immunology (2024)
The etiology and effect of age-related immune dysfunction in cancer is not completely understood. Here we show that limited priming of CD8 + T cells in the aged tumor microenvironment (TME) outweighs cell-intrinsic defects in limiting tumor control. Increased tumor growth in aging is associated with reduced CD8 + T cell infiltration and function. Transfer of T cells from young mice does not restore tumor control in aged mice owing to rapid induction of T cell dysfunction. Cell-extrinsic signals in the aged TME drive a tumor-infiltrating age-associated dysfunctional (T TAD ) cell state that is functionally, transcriptionally and epigenetically distinct from canonical T cell exhaustion. Altered natural killer cell-dendritic cell-CD8 + T cell cross-talk in aged tumors impairs T cell priming by conventional type 1 dendritic cells and promotes T TAD cell formation. Aged mice are thereby unable to benefit from therapeutic tumor vaccination. Critically, myeloid-targeted therapy to reinvigorate conventional type 1 dendritic cells can improve tumor control and restore CD8 + T cell immunity in aging.
Keyphrases
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