Uncoupled biological and chronological aging of neutrophils in cancer promotes tumor progression
Laura Mittmann, Florian Haring, Johanna Schaubächer, Roman Hennel, Bojan Smiljanov, Gabriele Zuchtriegel, Martin Canis, Olivier Gires, Fritz Krombach, Lesca M. Holdt, Sven Brandau, Thomas Vogl, Kirsten Lauber, Bernd Uhl, Christoph A. Reichel
Abstract
BACKGROUND: Beyond their fundamental role in homeostasis and host defense, neutrophilic granulocytes (neutrophils) are increasingly recognized to contribute to the pathogenesis of malignant tumors. Recently, aging of mature neutrophils in the systemic circulation has been identified to be critical for these immune cells to properly unfold their homeostatic and anti-infectious functional properties. The role of neutrophil aging in cancer remains largely obscure. METHODS: assays, and human data, we sought to define the functional relevance of neutrophil aging in cancer. RESULTS: Here, we show that signals released during early tumor growth accelerate biological aging of circulating neutrophils, hence uncoupling biological from chronological aging of these immune cells. This facilitates the accumulation of highly reactive neutrophils in malignant lesions and endows them with potent protumorigenic functions, thus promoting tumor progression. Counteracting uncoupled biological aging of circulating neutrophils by blocking the chemokine receptor CXCR2 effectively suppressed tumor growth. CONCLUSIONS: Our data uncover a self-sustaining mechanism of malignant neoplasms in fostering protumorigenic phenotypic and functional changes in circulating neutrophils. Interference with this aberrant process might therefore provide a novel, already pharmacologically targetable strategy for cancer immunotherapy.