In the tumor host,neutrophils may exhibit protumor or antitumor activity.It is hypothesized that in response to host-derived or therapy-induced factors,neutrophils adopt diverse functional states to ultimately execute...In the tumor host,neutrophils may exhibit protumor or antitumor activity.It is hypothesized that in response to host-derived or therapy-induced factors,neutrophils adopt diverse functional states to ultimately execute these differential functions.Here,we provide an alternative scenario in which the response of an individual tumor cell population determines the overall protumor versus antitumor outcome of neutrophil‒tumor interactions.Experimentally,we show that human neutrophils,which are sequentially stimulated with bacteria and secreted factors from tumor cells,kill a certain proportion of tumor target cells.However,the majority of the tumor cells remained resistant to this neutrophil-mediated killing and underwent a functional,phenotypic and transcriptomic switch that was reminiscent of partial epithelial‒to-mesenchymal transition.This cell biological switch was associated with physical escape from NK-mediated killing and resulted in enhanced metastasis to the lymph nodes in a preclinical orthotopic mouse model.Mechanistically,we identified the antimicrobial neutrophil granule proteins neutrophil elastase(NE)and matrix metalloprotease-9(MMP-9)as the molecular mediators of this functional switch.We validated these data in patients with head and neck cancer and identified bacterially colonized intratumoral niches that were enriched for mesenchymal tumor cells and neutrophils expressing NE and MMP-9.Our data reveal the parallel execution of tumor cytotoxic and prometastatic activity by activated neutrophils and identify NE and MMP-9 as mediators of lymph node metastasis.The identified mechanism explains the functional dichotomy of tumor-associated neutrophils at the level of the tumor target cell response and has implications for superinfected cancers and the dysbiotic tumor microenvironment.展开更多
基金supported by Marga and Walter Boll Stiftung,Deutsche Forschungsgemeinschaft(BR2278/8-1,HU 2795/2-1)TransRegio 332(project A4)Deutsche Krebshilfe and COST Action Mye-Infobank,supported by COST(European Cooperation in Science and Technology).
文摘In the tumor host,neutrophils may exhibit protumor or antitumor activity.It is hypothesized that in response to host-derived or therapy-induced factors,neutrophils adopt diverse functional states to ultimately execute these differential functions.Here,we provide an alternative scenario in which the response of an individual tumor cell population determines the overall protumor versus antitumor outcome of neutrophil‒tumor interactions.Experimentally,we show that human neutrophils,which are sequentially stimulated with bacteria and secreted factors from tumor cells,kill a certain proportion of tumor target cells.However,the majority of the tumor cells remained resistant to this neutrophil-mediated killing and underwent a functional,phenotypic and transcriptomic switch that was reminiscent of partial epithelial‒to-mesenchymal transition.This cell biological switch was associated with physical escape from NK-mediated killing and resulted in enhanced metastasis to the lymph nodes in a preclinical orthotopic mouse model.Mechanistically,we identified the antimicrobial neutrophil granule proteins neutrophil elastase(NE)and matrix metalloprotease-9(MMP-9)as the molecular mediators of this functional switch.We validated these data in patients with head and neck cancer and identified bacterially colonized intratumoral niches that were enriched for mesenchymal tumor cells and neutrophils expressing NE and MMP-9.Our data reveal the parallel execution of tumor cytotoxic and prometastatic activity by activated neutrophils and identify NE and MMP-9 as mediators of lymph node metastasis.The identified mechanism explains the functional dichotomy of tumor-associated neutrophils at the level of the tumor target cell response and has implications for superinfected cancers and the dysbiotic tumor microenvironment.
