Analyzing samples from patients with TNBC before and after treatment with neoadjuvant anti-PD-1, Fu, Jin, He, Chen, and Yang et al. found that enrichment for IFN-induced senescent CD8+ T cells predicted non-response in patients with early-stage TNBC. In mechanistic studies, IFN from HLA-DR+ monocytes triggered the IFN-IRF9-PARP axis in CD8+ T cells, resulting in excessive NAD+ consumption and senescence (reduced cytotoxicity and reduced responsiveness to anti-PD-1). Treatment with nicotinamide mononucleotide (an NAD+ precursor) reversed this senescence and restored the efficacy of anti-PD-1 in various models.
Contributed by Lauren Hitchings
ABSTRACT: 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.
Author Info: (1) Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Precision Cancer Medicine Center, Fudan University Shanghai Cancer Center, Shanghai 200032, P. R. Chi
Author Info: (1) Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Precision Cancer Medicine Center, Fudan University Shanghai Cancer Center, Shanghai 200032, P. R. China. (2) Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Precision Cancer Medicine Center, Fudan University Shanghai Cancer Center, Shanghai 200032, P. R. China. (3) Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Precision Cancer Medicine Center, Fudan University Shanghai Cancer Center, Shanghai 200032, P. R. China. (4) Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Precision Cancer Medicine Center, Fudan University Shanghai Cancer Center, Shanghai 200032, P. R. China. (5) Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Precision Cancer Medicine Center, Fudan University Shanghai Cancer Center, Shanghai 200032, P. R. China. (6) Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Precision Cancer Medicine Center, Fudan University Shanghai Cancer Center, Shanghai 200032, P. R. China. (7) Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Precision Cancer Medicine Center, Fudan University Shanghai Cancer Center, Shanghai 200032, P. R. China. (8) Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Precision Cancer Medicine Center, Fudan University Shanghai Cancer Center, Shanghai 200032, P. R. China. (9) Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Precision Cancer Medicine Center, Fudan University Shanghai Cancer Center, Shanghai 200032, P. R. China. (10) Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Precision Cancer Medicine Center, Fudan University Shanghai Cancer Center, Shanghai 200032, P. R. China. (11) Department of Immunology, Shanghai Medical School, and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, P. R. China. (12) Shanghai Fifth People's Hospital, Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Fudan University, Shanghai 201100, P. R. China. (13) Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Precision Cancer Medicine Center, Fudan University Shanghai Cancer Center, Shanghai 200032, P. R. China. Shanghai Academy of Natural Sciences (SANS), Fudan University, Shanghai 201203, P. R. China. (14) Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Precision Cancer Medicine Center, Fudan University Shanghai Cancer Center, Shanghai 200032, P. R. China.
