2. Academic Validation
  3. The tumor-derived cytokine Chi3l1 induces neutrophil extracellular traps that promote T cell exclusion in triple-negative breast cancer

The tumor-derived cytokine Chi3l1 induces neutrophil extracellular traps that promote T cell exclusion in triple-negative breast cancer

  • Immunity. 2023 Nov 18:S1074-7613(23)00483-1. doi: 10.1016/j.immuni.2023.11.002.
Tarek Taifour 1,  Sherif Samer Attalla 2,  Dongmei Zuo 3,  Yu Gu 2,  Virginie Sanguin-Gendreau 3,  Hailey Proud 2,  Emilie Solymoss 1,  Tung Bui 3,  Hellen Kuasne 3,  Vasilios Papavasiliou 3,  Chun Geun Lee 4,  Suchitra Kamle 4,  Peter M Siegel 5,  Jack A Elias 4,  Morag Park 5,  William J Muller 6
Affiliations

Affiliations

  • 1 McGill University, Division of Experimental Medicine, Department of Medicine, Faculty of Medicine, Montreal, QC H4A 3J1, Canada; Goodman Cancer Institute, Montreal, QC H3A 1A3, Canada.
  • 2 Goodman Cancer Institute, Montreal, QC H3A 1A3, Canada; McGill University, Department of Biochemistry, Faculty of Medicine, Montreal, QC H3A 1A3, Canada.
  • 3 Goodman Cancer Institute, Montreal, QC H3A 1A3, Canada.
  • 4 Brown University, Molecular Biology and Immunology, Faculty of Medicine, Providence, RI 02903, USA.
  • 5 McGill University, Division of Experimental Medicine, Department of Medicine, Faculty of Medicine, Montreal, QC H4A 3J1, Canada; Goodman Cancer Institute, Montreal, QC H3A 1A3, Canada; McGill University, Department of Biochemistry, Faculty of Medicine, Montreal, QC H3A 1A3, Canada.
  • 6 McGill University, Division of Experimental Medicine, Department of Medicine, Faculty of Medicine, Montreal, QC H4A 3J1, Canada; Goodman Cancer Institute, Montreal, QC H3A 1A3, Canada; McGill University, Department of Biochemistry, Faculty of Medicine, Montreal, QC H3A 1A3, Canada. Electronic address: william.muller@mcgill.ca.
PMID: 38039967 DOI: 10.1016/j.immuni.2023.11.002
Abstract

In triple-negative breast Cancer (TNBC), stromal restriction of CD8+ T cells associates with poor clinical outcomes and lack of responsiveness to immune-checkpoint blockade (ICB). To identify mediators of T cell stromal restriction, we profiled murine breast tumors lacking the transcription factor STAT3, which is commonly hyperactive in breast cancers and promotes an immunosuppressive tumor microenvironment. Expression of the cytokine Chi3l1 was decreased in STAT3-/- tumors. CHI3L1 expression was elevated in human TNBCs and Other solid tumors exhibiting T cell stromal restriction. Chi3l1 ablation in the polyoma virus middle T (PyMT) breast Cancer model generated an anti-tumor immune response and delayed mammary tumor onset. These effects were associated with increased T cell tumor infiltration and improved response to ICB. Mechanistically, Chi3l1 promoted neutrophil recruitment and neutrophil extracellular trap formation, which blocked T cell infiltration. Our findings provide insight into the mechanism underlying stromal restriction of CD8+ T cells and suggest that targeting Chi3l1 may promote anti-tumor immunity in various tumor types.

Keywords

Chi3l1; NETosis; T cell stromal restriction; TNBC; breast cancer; immune microenvironment; immunotherapy; mouse models; neutrophils.

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