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Spatially distinct tumor immune microenvironments stratify triple-negative breast cancers
Tina Gruosso, … , Benjamin Haibe-Kains, Morag Park
Tina Gruosso, … , Benjamin Haibe-Kains, Morag Park
Published February 12, 2019
Citation Information: J Clin Invest. 2019;129(4):1785-1800. https://doi.org/10.1172/JCI96313.
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Research Article Oncology

Spatially distinct tumor immune microenvironments stratify triple-negative breast cancers

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Abstract

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 (IDO) 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.

Authors

Tina Gruosso, Mathieu Gigoux, Venkata Satya Kumar Manem, Nicholas Bertos, Dongmei Zuo, Irina Perlitch, Sadiq Mehdi Ismail Saleh, Hong Zhao, Margarita Souleimanova, Radia Marie Johnson, Anne Monette, Valentina Muñoz Ramos, Michael Trevor Hallett, John Stagg, Réjean Lapointe, Atilla Omeroglu, Sarkis Meterissian, Laurence Buisseret, Gert Van den Eynden, Roberto Salgado, Marie-Christine Guiot, Benjamin Haibe-Kains, Morag Park

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Figure 6

Fully inflamed TNBC are associated with a proinflammatory TIME.

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Fully inflamed TNBC are associated with a proinflammatory TIME.
(A and B...
(A and B) Heatmap depicting the expression of genes associated with a type 1 IFN response and cytotoxic activity in the tumor stroma (A) and epithelium (B) (n = 22). (C) Representative images showing a higher number of GzmB+ CD8+ T cells in FI tumor epithelium compared with numbers in SR tumor. Pan-cytokeratin (Pan-CK) staining (pink) identifies tumor cells, and DAPI (blue) identifies nuclei. White squares outline the position of the zoomed area in the stromal region for SR tumor and the epithelial region for FI tumor. Scale bars: 50 μm (merge, CD8, and GzmB) and 5 μm (enlarged insets showing CD8 and GzmB colocalization). n = 22. (D) Quantification of GzmB+CD8+ T cells in the tumor core, tumor stroma, and tumor epithelium (n = 32). Data were analyzed using the Kruskal-Wallis test. Data represent the mean ± SEM. (E) GzmB+CD8+ T cell density in tumor epithelium was positively correlated with epiCD8 (n = 20). Data were analyzed using Spearman’s correlation. Green, blue, and red dots represent MR, SR, and FI tumors, respectively.

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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