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Updated: Jan 18, 2026
Multiplexed Immunofluorescence Analysis and Quantification of Intratumoral PD-1+ Tim-3+ CD8+ T Cells
Published on: February 8, 2018
Interferon-induced senescent CD8+ T cells reduce anti-PD1 immunotherapy efficacy in early triple-negative breast
1Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Precision Cancer Medicine Center, Fudan University Shanghai Cancer Center, Shanghai 200032, P. R. China.
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.
Insights
Researchers found that interferon-induced senescent CD8+ T cells drive immunotherapy nonresponse in early triple-negative breast cancer (TNBC). Nicotinamide mononucleotide treatment restored T cell function and improved immunotherapy efficacy.
Area of Science:
- Immunology
- Oncology
- Cellular Biology
Background:
- Triple-negative breast cancer (TNBC) lacks biomarkers for immunotherapy guidance, particularly in early stages.
- Current immunotherapy strategies face challenges in predicting patient response.
Purpose of the Study:
- To identify biomarkers predicting immunotherapy response in early-stage TNBC.
- To elucidate mechanisms of immunotherapy nonresponsiveness.
- To develop strategies to enhance immunotherapy efficacy.
Main Methods:
- Single-cell RNA sequencing, bulk transcriptomics, and pathology assays on 171 early-stage TNBC patient samples.
- Investigation of interferon (IFN)-induced CD8+ T cell subsets.
- Analysis of monocyte-derived IFN and its effect on T cell senescence.
- Assessment of nicotinamide mononucleotide (NMN) treatment in preclinical models.
Main Results:
- An enriched subset of interferon (IFN)-induced CD8+ T cells was identified, predicting immunotherapy nonresponsiveness.
- IFN from HLA-DR+ monocytes induced CD8+ T cell senescence, characterized by NAD+ consumption and reduced cytotoxicity.
- NMN treatment reversed T cell senescence and improved immunotherapy efficacy in organoid-T cell cocultures and mouse models.
Conclusions:
- Interferon-induced T cell senescence is a key mechanism of immunotherapy nonresponsiveness in early TNBC.
- Nicotinamide mononucleotide represents a potential therapeutic strategy to restore CD8+ T cell function and enhance immunotherapy outcomes in TNBC.
