Journal Article

Spatially distinct tumor immune microenvironments stratify triple-negative breast cancers

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

2019

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: Analysis / Apoptosis / B7 antigen / B7-H1 Antigen - immunology / Biochemistry / Biomarkers / Biomedical research / Breast cancer / Cancer therapies / Cancer treatment / Care and treatment / CD8 antigen / CD8-Positive T-Lymphocytes - immunology / CD8-Positive T-Lymphocytes - pathology / Cell death / Chemotherapy / Cholesterol / Cholesterol - immunology / Colorectal cancer / Female / Gene expression / Genes / Genetic aspects / Granzyme B / Granzymes - immunology / Health aspects / Humans / Immune checkpoint / Immune system / Immunomodulation / Interferon / Interferon Type I - immunology / Ligands / Localization / Lymphocytes / Lymphocytes B / Lymphocytes T / Medical prognosis / Metastases / Microenvironments / Outcome and process assessment (Medical care) / Ovarian cancer / Oxidative stress / PD-L1 protein / Risk factors / Spatial discrimination / Stroma / T cells / Therapeutic applications / Triple Negative Breast Neoplasms - immunology / Triple Negative Breast Neoplasms - pathology / Tryptophan 2,3-dioxygenase / Tumor Microenvironment - immunology / Tumors