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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 8

SR TNBC tumors are defined by a cholesterol gene expression signature and a distinct TIME.

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SR TNBC tumors are defined by a cholesterol gene expression signature an...
(A) Heatmap depicting the expression of genes of the SPP of cholesterol biosynthesis in bulk tumor from SR and FI tumors (n = 22). (B) Signature score of genes depicted in (A). Data were analyzed with Spearman’s correlation. (C) Signature score of ISGs repressed by SREBP2 showing decreased expression in SR versus FI tumors (n = 22). Data were analyzed with Spearman’s correlation. (D) Representative IHF images showing the presence of IL-17–producing cells in the tumor stroma of SR and FI tumors (n = 22). Blue, DAPI; pink, pan-CK; yellow, IL-17F. White squares represent the zoomed position in the images. Scale bars: 50 μm (merge) and 20 μm (enlarged insets). (E and F) Density of IL-17–producing cells (E) and neutrophils (F) across SR and FI tumors (n = 10; 5 patients with the lowest and 5 patients with the highest epiCD8, respectively, for SR and FI tumors). Data were analyzed by Mann-Whitney U test and represent the mean ± SEM.

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

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