Interferon-induced senescent CD8+ T cells reduce anti-PD1 immunotherapy efficacy in early triple-negative breast cancer
Menée à l'aide de modèles murins et d'échantillons tumoraux prélevés sur 171 patientes atteintes d'un cancer du sein triple négatif de stade précoce et recevant une chimiothérapie en combinaison ou non avec une immunothérapie, cette étude met en évidence un mécanisme par lequel l'interféron, produit par des monocytes HLA DR+, réduit l'efficacité des anti-PD1 en induisant la sénescence de lymphocytes T CD8+
Triple-negative breast cancers (TNBCs) lack predictive biomarkers to guide immunotherapy, especially during early-stage disease. To address this issue, we used single-cell RNA sequencing, bulk transcriptomics, and pathology assays on samples from 171 patients with early-stage TNBC receiving chemotherapy with or without immunotherapy. Our investigation identified an enriched subset of interferon (IFN)–induced CD8+ T cells in early TNBC samples, which predict immunotherapy nonresponsiveness. Mechanistically, IFN produced by HLA-DR+ monocytes triggered cellular senescence in CD8+ T cells, which was marked by excessive NAD+ consumption, reduced cytotoxicity, and immunotherapy nonresponsiveness. Nicotinamide mononucleotide treatment restored the function of IFN-induced senescent CD8+ T cells and enhanced immunotherapy efficacy in patient-derived organoid–T cell coculture and in mouse models. Overall, our study identifies IFN-induced T cell senescence as a driver of immunotherapy nonresponsiveness in early TNBC and provides a strategy to restore CD8+ T cell function for immunotherapeutic benefit.
Science Translational Medicine , résumé, 2025