期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 129, 期 4, 页码 1785-1800出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI96313
关键词
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资金
- CQDM (Consortium Quebecois sur la decouverte du medicament [Quebec Consortium for Drug Discovery])
- NIH [5P01CA097189-08]
- Stand Up 2 Cancer (SU2C) [106244.4 FC: 410006066]
- Merck Sharpe Dohme Corp.
- McGill Faculty of Medicine Grants for Translational Research
- Database and Tissue Bank Axis of the Reseau de Recherche en Cancer of the Fonds de Recherche du Quebec-Sante
- Quebec Breast Cancer Foundation
- Canderel and Charlotte fellowship
- Leo Karassik Oncology fellowship
Understanding the tumor immune microenvironment (TIME) promises to be key for optimal cancer therapy, especially in triple-negative breast cancer (TNBC). Integrating spatial resolution of immune cells with laser capture microdissection gene expression profiles, we defined distinct TIME stratification in TNBC, with implications for current therapies including immune checkpoint blockade. TNBCs with an immunoreactive microenvironment exhibited tumoral infiltration of granzyme B(+)CD8(+) T cells (GzmB(+)CD8(+) T cells), a type 1 IFN signature, and elevated expression of multiple immune inhibitory molecules including indoleamine 2,3-dioxygenase (IGO) and programmed cell death ligand 1 (PD-L1), and resulted in good outcomes. An immune-cold microenvironment with an absence of tumoral CD8(+) T cells was defined by elevated expression of the immunosuppressive marker B7-H4, signatures of fibrotic stroma, and poor outcomes. A distinct poor-outcome immunomodulatory microenvironment, hitherto poorly characterized, exhibited stromal restriction of CD8(+) T cells, stromal expression of PD-L1, and enrichment for signatures of cholesterol biosynthesis. Metasignatures defining these TIME subtypes allowed us to stratify TNBCs, predict outcomes, and identify potential therapeutic targets for TNBC.
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