The GM-CSF–IRF5 signaling axis in eosinophils promotes antitumor immunity through activation of type 1 T cell responses

• Published in: The Journal of experimental medicine Vol. 217; no. 12
• Main Authors: Arnold, Isabelle C., Artola-Boran, Mariela, Gurtner, Alessandra, Bertram, Katrin, Bauer, Michael, Frangez, Ziva, Becher, Burkhard, Kopf, Manfred, Yousefi, Shida, Simon, Hans-Uwe, Tzankov, Alexandar, Müller, Anne
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 07.12.2020
• Subjects: Adenoma - drug therapy; Adenoma - immunology; Adenoma - pathology; Animals; Carcinogenesis - drug effects; Carcinogenesis - pathology; Cell Line, Tumor; Cell Proliferation - drug effects; Colonic Neoplasms - drug therapy; Colonic Neoplasms - immunology; Colonic Neoplasms - pathology; Eosinophils - drug effects; Eosinophils - metabolism; Eosinophils - pathology; Female; Granulocyte-Macrophage Colony-Stimulating Factor - metabolism; Humans; Immune Checkpoint Inhibitors - pharmacology; Immune Checkpoint Inhibitors - therapeutic use; Immunity - drug effects; Interferon Regulatory Factors - metabolism; Interleukin-10 - metabolism; Interleukin-5 - metabolism; Intestines - pathology; Lymph Nodes - drug effects; Lymph Nodes - pathology; Lymphocyte Activation - drug effects; Lymphocyte Activation - immunology; Male; Mice, Inbred C57BL; Mucosal Immunology; Neoplasms - immunology; Neoplasms - metabolism; Neoplasms - pathology; Signal Transduction - drug effects; STAT3 Transcription Factor - metabolism; Survival Analysis; Th1 Cells - drug effects; Th1 Cells - immunology; Transcription, Genetic - drug effects; Transgenes; Tumor Immunology; Tumor Microenvironment - drug effects
• ISSN: 0022-1007; 1540-9538; 1540-9538
• DOI: 10.1084/jem.20190706

The depletion of eosinophils represents an efficient strategy to alleviate allergic asthma, but the consequences of prolonged eosinophil deficiency for human health remain poorly understood. We show here that the ablation of eosinophils severely compromises antitumor immunity in syngeneic and genetic models of colorectal cancer (CRC), which can be attributed to defective Th1 and CD8+ T cell responses. The specific loss of GM-CSF signaling or IRF5 expression in the eosinophil compartment phenocopies the loss of the entire lineage. GM-CSF activates IRF5 in vitro and in vivo and can be administered recombinantly to improve tumor immunity. IL-10 counterregulates IRF5 activation by GM-CSF. CRC patients whose tumors are infiltrated by large numbers of eosinophils also exhibit robust CD8 T cell infiltrates and have a better prognosis than patients with eosinophillow tumors. The combined results demonstrate a critical role of eosinophils in tumor control in CRC and introduce the GM-CSF–IRF5 axis as a critical driver of the antitumor activities of this versatile cell type.