Blomberg et al. demonstrated that ICB promotes CD4+ T cell-mediated IL-5 production that drives eosinophil expansion and response to immunotherapy. ICB-responding patients with TNBC showed systemic eosinophil expansion and increased intratumoral eosinophil- and CD8+ T cell-related gene signatures. In primary and metastatic breast cancer models, ICB synergized with cisplatin to induce IL-5-dependent systemic eosinophil expansion, CD8+ T cell activation, and response to therapy. IL-33 increased intratumoral eosinophil infiltration, and recombinant IL-33 therapy engaged eosinophils and enhanced ICB response.
Contributed by Shishir Pant
ABSTRACT: Immune checkpoint blockade (ICB) has heralded a new era in cancer therapy. Research into the mechanisms underlying response to ICB has predominantly focused on T cells; however, effective immune responses require tightly regulated crosstalk between innate and adaptive immune cells. Here, we combine unbiased analysis of blood and tumors from metastatic breast cancer patients treated with ICB with mechanistic studies in mouse models of breast cancer. We observe an increase in systemic and intratumoral eosinophils in patients and mice responding to ICB treatment. Mechanistically, ICB increased IL-5 production by CD4(+) T cells, stimulating elevated eosinophil production from the bone marrow, leading to systemic eosinophil expansion. Additional induction of IL-33 by ICB-cisplatin combination or recombinant IL-33 promotes intratumoral eosinophil infiltration and eosinophil-dependent CD8(+) T cell activation to enhance ICB response. This work demonstrates the critical role of eosinophils in ICB response and provides proof-of-principle for eosinophil engagement to enhance ICB efficacy.
Author Info: (1) Division of Tumor Biology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands; Department of Immunology, Leid
Author Info: (1) Division of Tumor Biology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands; Department of Immunology, Leiden University Medical Centre, Leiden, the Netherlands. (2) Division of Tumor Biology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands. (3) Division of Tumor Biology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands. (4) Division of Tumor Biology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (5) Division of Tumor Biology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands; Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (6) Division of Tumor Biology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands; Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (7) Division of Tumor Biology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands. (8) Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands; Department of Gastrointestinal Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands; Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (9) Division of Tumor Biology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (10) Division of Tumor Biology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (11) Division of Tumor Biology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (12) Division of Tumor Biology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (13) Division of Tumor Biology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands. (14) Division of Tumor Biology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands. (15) Division of Tumor Biology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands. (16) Division of Tumor Biology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands. (17) Division of Tumor Biology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands. (18) Division of Tumor Biology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands; Department of Immunology, Leiden University Medical Centre, Leiden, the Netherlands. (19) VIB-UGent Center for Inflammation Research, Ghent University, Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium. (20) Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (21) Oncode Institute, Utrecht, the Netherlands; Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands; Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (22) Department of Thoracic Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (23) Department of Thoracic Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (24) Oncode Institute, Utrecht, the Netherlands; Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands; Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (25) VIB-UGent Center for Inflammation Research, Ghent University, Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium. (26) Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (27) Oncode Institute, Utrecht, the Netherlands; Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (28) Division of Tumor Biology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands; Department of Immunology, Leiden University Medical Centre, Leiden, the Netherlands. Electronic address: k.d.visser@nki.nl. (29) Division of Tumor Biology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands; Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. Electronic address: m.kok@nki.nl.
