Neutrophil elastase selectively kills cancer cells and attenuates tumorigenesis

Cui, Chang; Chakraborty, Kasturi; Tang, Xu; Zhou, Guolin; Schoenfelt, Kelly Q.; Becker, Kristen M.; Hoffman, Alexandria; Chang, Yung-Fu; Blank, Ariane; Reardon, Catherine A.; Kenny, Hilary A.; Vaisar, Tomáš; Lengyel, Ernst; Greene, Geoffrey L.; Becker, Lev

doi:10.1016/j.cell.2021.04.016

Cited by 164 publications

(141 citation statements)

References 51 publications

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“…It has been known that neutrophils are the most common immune cell in anti-inflammatory response and natural anti-tumor response processes, and elevated neutrophils usually implied that abnormal cell growth or pathogen infection. In previous study, Chang Cui et al found that neutrophil elastase selectively killed cancer cells and attenuated tumorigenesis 19 . Neutrophil-secreted elastase shows dramatic selectivity, inducing cell death in tumors and at metastatic sites in animal models while sparing proximal healthy cells, which further implied that neutrophil was a critical factor for the development and treatment of cancers.…”

Section: Resultsmentioning

confidence: 96%

Comprehensive analysis of Transcription Factors identified novel prognostic biomarker in human bladder cancer

et al. 2021

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Background: Transcriptional factors (TFs) are responsible for regulating the transcription of pro-oncogenes and tumor suppressor genes in the process of tumor development. However, the role of these transcription factors in Bladder cancer (BCa) remains unclear. And the main purpose of this research is to explore the possibility of these TFs serving as biomarkers for BCa. Methods: We analyzed the differential expression of TFs in BCa from The Cancer Genome Atlas (TCGA) online database, identified 408 up-regulated TFs and 751down-regulated TFs. We obtained some hub genes via WGCNA model and detected the RNAs level in BCa cells and tissues. Then, the relationship between the expression and clinicopathological parameters was further investigated. Kaplan-Meier curves and the log-rank test were carried out to analyze the relationship between NFATC1, AKNA and five-TFs combination and overall survival (OS). And RT-PCR assay was conducted to further consolidate and verify these results. Results: There were significant differences in the expression of five TFs (CBX7, AKNA, HDAC4, EBF2 and NFATC1) between bladder cancer and normal bladder tissue. In BCa tissue and cell lines, the five TFs were frequently down-regulated, and closely related to poor prognosis. Moreover, the RT-PCR results of five TFs in bladder cancer and normal bladder tissue were consistent with the database results, and reduced TFs could significantly induce or restrain the transcription of many critical factors. The expression level of AKNA and NFATC1 could serve as independent biomarker to predict the overall survival (P<0.05). And the above five TFs combined detection of bladder cancer has higher sensitivity and specificity. Furthermore, differential neutrophils expression between high-risk and low-risk were found, which consolidated the role and function of the five TFs combination model in the progression of BCa. Conclusions: Our analysis effectively provides a newly TFs-associated prognostic model for bladder cancer. The combination of five identified-TFs is an independent prognostic biomarker, which could serve as a more effective therapeutic target for BCa patients.

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Section: Resultsmentioning

confidence: 96%

Comprehensive analysis of Transcription Factors identified novel prognostic biomarker in human bladder cancer

et al. 2021

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“…Overall, these experiments suggest that tumor CCL5 not only enhances the number of EVs but also alters the cargo of EVs. Analysis of these differentially expressed cytokines indicated that pro-metastatic osteopontin (OPN) [ 44 ] and SLPI [ 45 , 46 , 47 , 48 ] in both TEMs (in vitro) and TAMs (in vivo) are most strongly induced by tumor CCL5 . Our previous work had established OPN and SLPI as markers of macrophages activated by CCL5 [ 11 ], and both of these factors have been shown to directly regulate tumor cell invasiveness [ 44 , 45 , 46 , 47 , 48 ].…”

Section: Resultsmentioning

confidence: 99%

“…Analysis of these differentially expressed cytokines indicated that pro-metastatic osteopontin (OPN) [ 44 ] and SLPI [ 45 , 46 , 47 , 48 ] in both TEMs (in vitro) and TAMs (in vivo) are most strongly induced by tumor CCL5 . Our previous work had established OPN and SLPI as markers of macrophages activated by CCL5 [ 11 ], and both of these factors have been shown to directly regulate tumor cell invasiveness [ 44 , 45 , 46 , 47 , 48 ]. These data represent a positive feedback loop between tumor and macrophage mediated by CCL5 and EVs ( Figure 5 D).…”

Section: Resultsmentioning

confidence: 99%

“…These findings further demonstrate that CCL5 plays a novel role, through EVs, in altering macrophage function rather than just recruitment. Macrophages altered by tumor CCL5 expression and EVs have increased expression of several genes known to drive invasion and metastasis, including OPN [ 44 ], SLPI [ 45 , 46 , 47 , 48 ], HGF [ 43 ], and NRG3 [ 50 ]. There are several possible reasons why activation by CCL5-stimulated EVs rather than direct CCL5 interaction is required to educate tumor-recruited macrophages.…”

Section: Discussionmentioning

confidence: 99%

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Tumor Extracellular Vesicles Regulate Macrophage-Driven Metastasis through CCL5

Rabe

Walker

Rustandy

et al. 2021

Cancers

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Purpose: To understand how tumor cells alter macrophage biology once they are recruited to triple-negative breast cancer (TNBC) tumors by CCL5. Method: Mouse bone marrow derived macrophage (BMDMs) were isolated and treated with recombinant CCL5 protein alone, with tumor cell conditioned media, or with tumor extracellular vesicles (EVs). Media from these tumor EV-educated macrophages (TEMs) was then used to determine how these macrophages affect TNBC invasion. To understand the mechanism, we assayed the cytokine secretion from these macrophages to determine how they impact tumor cell invasion. Tumor CCL5 expression was varied in tumors to determine its role in regulating macrophage biology through EVs. Results: Tumor EVs are a necessary component for programming naïve macrophages toward a pro-metastatic phenotype. CCL5 expression in the tumor cells regulates both EV biogenesis/secretion/cargo and macrophage EV-education toward a pro-metastatic phenotype. Analysis of the tumor EV-educated macrophages (TEMs) showed secretion of a variety of factors including CXCL1, CTLA-4, IFNG, OPN, HGF, TGFB, and CCL19 capable of remodeling the surrounding tumor stroma and immune infiltrate. Injection of tumor cells with macrophages educated by metastatic tumor cell EVs into mice increased tumor metastasis to the lung. Conclusion: These results demonstrate that tumor-derived EVs are key mediators of macrophage education and likely play a more complex role in modulating tumor therapeutic response by regulating the tumor immune infiltrate.

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“…7b). ELANE has been reported to have an anti-cancer function in human neutrophils 80 . Taken together, these results suggested that the neutrophils in the TME are dominated by immunosuppressive phenotypes, with aged neutrophils showed moderate anti-tumor and antigen-presenting functions.…”

Section: Therapy Induced Remodeling Of Mature Neutrophils Into Aged Phenotypementioning

confidence: 99%

Single-Cell RNA Sequencing Reveals Tumor Microenvironment Remodeling after Neoadjuvant Immunotherapy in Non-small Cell Lung Cancer

Hu¹,

zhang²,

Xia³

et al. 2021

Preprint

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Immunotherapy has revolutionized cancer treatment, but most patients are refractory to immunotherapy or acquire resistance. To explore immunotherapy resistance mechanisms, we characterized the transcriptomes of ~92000 single cells from 15 patients with non-small cell lung cancer (NSCLC) during neoadjuvant PD-1 blockade combined with chemotherapy. CD8+ T, natural killer, B, and dendritic cells were activated by therapy. Therapy also promoted differentiation of memory T cells into effector T cells. Macrophages were remodeled into an M0-like phenotype and neutrophils into an aged phenotype. Distinct therapy-induced cancer-cell transcriptomes were associated with clinical response. Major pathologic responders (MPRs) activated antigen presentation via major histocompatibility complex class II (MHC-II). Cancer cells of non-MPRs exhibited overexpression of estrogen metabolism enzymes and elevated serum estradiol. Elevated estradiol activated EGFR signaling and upregulated the expression of VEGFA, which promoted an immunosuppressive microenvironment. FCRL4+FCRL5+ memory B cells and CD16+CX3CR1+ monocytes were identified as biomarkers for positive immunotherapy response.

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Neutrophil elastase selectively kills cancer cells and attenuates tumorigenesis

Cited by 164 publications

References 51 publications

Comprehensive analysis of Transcription Factors identified novel prognostic biomarker in human bladder cancer

Comprehensive analysis of Transcription Factors identified novel prognostic biomarker in human bladder cancer

Tumor Extracellular Vesicles Regulate Macrophage-Driven Metastasis through CCL5

Single-Cell RNA Sequencing Reveals Tumor Microenvironment Remodeling after Neoadjuvant Immunotherapy in Non-small Cell Lung Cancer

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