Uncoupled biological and chronological aging of neutrophils in cancer promotes tumor progression

Abstract

BackgroundBeyond 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.MethodsEmploying advanced in vivo microscopy techniques in different animal models of cancer as well as utilizing pulse-labeling and cell transfer approaches, various ex vivo/in vitro assays, and human data, we sought to define the functional relevance of neutrophil aging in cancer.ResultsHere, 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.ConclusionsOur 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.

The ‘Danse Macabre’—Neutrophils the Interactive Partner Affecting Oral Cancer Outcomes

“…Recently, it has been shown that uncoupled biological and chronological aging of neutrophils contributes to the progression of cancer and promotes advanced stages of malignant disease ( 82 ). Using a mouse squamous cell carcinoma cell line (SCC VII), we showed a noteworthy positive association between the RNA expression levels of formyl peptide receptor 1 (FPR1), an established marker gene of neutrophils, and of C-X-C motif chemokine receptor 4 (CXCR4), whose gene product increases during neutrophil aging on the surface of these immune cells, with higher tumor stages ( 83 , 84 ). Activation of the NLRP3 inflammasome in perivascular macrophages by tumor-released Damage-associated molecular patterns (DAMPs) such as S100A8/9 induce the synthesis of inflammatory mediators that upregulate adhesion and signaling molecules on the surface of microvascular endothelial cells, in turn promoting the trafficking of aged neutrophils to the perivascular space ( 84 ).…”

“…Activation of the NLRP3 inflammasome in perivascular macrophages by tumor-released Damage-associated molecular patterns (DAMPs) such as S100A8/9 induce the synthesis of inflammatory mediators that upregulate adhesion and signaling molecules on the surface of microvascular endothelial cells, in turn promoting the trafficking of aged neutrophils to the perivascular space ( 84 ). Following antibody-mediated depletion of aged neutrophils, a significant decrease in the growth of tumors was observed in experimental HNSCC ( 84 ). Aged neutrophils are related to a more pro-tumorigenic state.…”

“…Aged neutrophils are related to a more pro-tumorigenic state. They support cancer cell proliferation via the release of neutrophil elastase ( 84 , 85 ). The neutrophil-to-lymphocyte ratio (NLR) has recently been introduced as a better prognostic factor for survival in several types of solid tumors, including OSCC ( 86 – 89 ), as opposed to neutrophil levels alone ( 90 ), although the mechanisms involved in high NLRs (typically >3) are yet to be determined ( 91 , 92 ).…”

Circulating Ageing Neutrophils as a Marker of Asymptomatic Polyvascular Atherosclerosis in Statin-Naïve Patients without Established Cardiovascular Disease

“…It has been established that large eccentric plaques and plaques with high inflammatory activity intensively accumulate CXCR4-expressing cells from the systemic circulation [ 31 , 32 ]. In addition, it is possible that as polyvascular atherosclerosis progresses, there is an increase in the systemic circulation of signaling molecules that trigger excessive and accelerated neutrophil aging, something that has been recently described as occurring in malignant tumors and HIV infections [ 33 , 34 , 35 ].…”

A microfluidic model of human vascularized breast cancer metastasis to bone for the study of neutrophil-cancer cell interactions

“…Since the identification of TANs, the interplay between CCs and neutrophils was mainly investigated through the analysis of patient samples [ 16 ] and in vivo models [ 17 , 18 ]. These approaches led for instance to the development of innovative strategies to impair neutrophil migration and recruitment to the tumor microenvironment [ 19 ].…”