Uncoupled biological and chronological ageing of neutrophils in HNSCC promotes tumor progression

Introduction Beyond their fundamental role in homeostasis and host defense, neutrophils contribute to the pathogenesis of head and neck squamous cell carcinoma (HNSCC). Recently, ageing 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 ageing in HNSCC remains obscure. Methods Employing in vivo microscopy techniques in different mouse models as well as utilizing pulse-labeling/cell-transfer approaches, and ex vivo / in vitro assays, we sought to define the functional relevance of neutrophil ageing in HNSCC. Results Signals released during early tumor growth accelerate biological ageing of circulating neutrophils, hence uncoupling biological from chronological ageing of these immune cells. This facilitates the accumulation of highly reactive neutrophils in malignant lesions and endows them with pro-tumorigenic functions, thus promoting tumor progression. Counteracting uncoupled biological ageing of circulating neutrophils by blocking the chemokine receptor CXCR2 effectively suppressed tumor growth. Conclusions Our data uncover a self-sustaining mechanism of HNSCC in fostering pro-tumorigenic phenotypic and functional changes in circulating neutrophils. Interference with this aberrant process might provide a novel, already pharmacologically targetable strategy for HNSCC immunotherapy. Deutsche Forschungsgemeinschaft (SFB 914) Publication History Article published online: 24 May 2022 © 2022. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/). Georg Thieme Verlag Rüdigerstraße 14, 70469 Stuttgart, Germany