Xerostomia is a severe side effect of radiation therapy in head and neck cancer patients. To date, no satisfactory treatment option has been established. Because mesenchymal stem cells（MSCs） have been identified as ...Xerostomia is a severe side effect of radiation therapy in head and neck cancer patients. To date, no satisfactory treatment option has been established. Because mesenchymal stem cells（MSCs） have been identified as a potential treatment modality, we aimed to evaluate stem cell distribution following intravenous and intraglandular injections using a surgical model of salivary gland damage and to analyse the effects of MSC injections on the recruitment of immune cells. The submandibular gland ducts of rats were surgically ligated. Syngeneic adult MSCs were isolated, immortalised by simian virus 40（SV40） large T antigen and characterized by flow cytometry. MSCs were injected intravenously and intraglandularly. After 1, 3 and 7 days, the organs of interest were analysed for stem cell recruitment. Inflammation was analysed by immunohistochemical staining. We were able to demonstrate that, after intravenous injection, MSCs were recruited to normal and damaged submandibular glands on days 1, 3 and 7. Unexpectedly, stem cells were recruited to ligated and non-ligated glands in a comparable manner. After intraglandular injection of MSCs into ligated glands, the presence of MSCs, leucocytes and macrophages was enhanced, compared to intravenous injection of stem cells. Our data suggest that injected MSCs were retained within the inflamed glands, could become activated and subsequently recruited leucocytes to the sites of tissue damage.展开更多
INTRODUCTION Organic material （e.g. nuts in children and bones or food in adults） is the most common foreign body inhaled by patients. Just one tenth of all foreign bodies in the airway are located in the larynx.L...INTRODUCTION Organic material （e.g. nuts in children and bones or food in adults） is the most common foreign body inhaled by patients. Just one tenth of all foreign bodies in the airway are located in the larynx.Laryngeal foreign bodies among adults are rarely seen but con be a life threatening event requiring immediate lifesaving intervention. Here, we report an unusual case of a 56-year-old male patient presenting with sudden dyspnea due to a fulminant onset of massive laryngeal swelling. After securing the airway by tracheostomy, an organic foreign body （a fragment of the patient＇s own teeth） was successfully removed by direct laryngoscopy under general anesthesia.展开更多
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
Neutrophils have emerged as key players in tumor progression and are often associated with poor prognosis.Despite ongoing efforts to target neutrophil functions in cancer,therapeutic success has been limited.In this s...Neutrophils have emerged as key players in tumor progression and are often associated with poor prognosis.Despite ongoing efforts to target neutrophil functions in cancer,therapeutic success has been limited.In this study,we addressed the possibility of blocking STAT3 signaling in neutrophils as a targeted therapeutic intervention in cancer.Conditional deletion of Stat3 in a neutrophil-specific manner(Ly6GcreStat3fl/fl mice)significantly impaired tumor growth and metastasis in mice.Neutrophils isolated from these mice exhibited a strong antitumoral phenotype,with increased MHCII,CD80/86 and ICAM-1 expression.Immune profiling of tumors and tumor-draining lymph nodes of these mice revealed significant enrichment of CD8^(+)T cells(granzymeB^(hi),perforin^(hi) and IFN-γ^(hi))with strong cytotoxic activity.To further translate these findings to human settings,we blocked STAT3 signaling in cancer patient neutrophils via the small molecule in^(hi)bitor LLL12 and assessed its effects on patient-derived tumor explants.In agreement with the in vivo mouse data,we observed the expansion and activation of cytotoxic CD8^(+)T cells in such explants.To test the therapeutic applicability of STAT3 targeting,we utilized myeloid cell-selective STAT3 antisense oligonucleotide(CpG-STAT3ASO)to target neutrophils in vivo in tumor-bearing mice.Consistent with previous results,neutrophil-specific STAT3 knockdown impaired tumor growth and enhanced cytotoxic T cell activity in the tumors and tumor-draining lymph nodes of treated mice.These findings highlight STAT3 signaling as a deleterious pathway supporting the protumoral activity of neutrophils and suggest that neutrophil-targeted STAT3 in^(hi)bition is a promising opportunity for cancer immunotherapy,providing novel insights into targeted therapeutic avenues.展开更多
基金supported by the Novartis Foundation for Therapeutic Research
文摘Xerostomia is a severe side effect of radiation therapy in head and neck cancer patients. To date, no satisfactory treatment option has been established. Because mesenchymal stem cells（MSCs） have been identified as a potential treatment modality, we aimed to evaluate stem cell distribution following intravenous and intraglandular injections using a surgical model of salivary gland damage and to analyse the effects of MSC injections on the recruitment of immune cells. The submandibular gland ducts of rats were surgically ligated. Syngeneic adult MSCs were isolated, immortalised by simian virus 40（SV40） large T antigen and characterized by flow cytometry. MSCs were injected intravenously and intraglandularly. After 1, 3 and 7 days, the organs of interest were analysed for stem cell recruitment. Inflammation was analysed by immunohistochemical staining. We were able to demonstrate that, after intravenous injection, MSCs were recruited to normal and damaged submandibular glands on days 1, 3 and 7. Unexpectedly, stem cells were recruited to ligated and non-ligated glands in a comparable manner. After intraglandular injection of MSCs into ligated glands, the presence of MSCs, leucocytes and macrophages was enhanced, compared to intravenous injection of stem cells. Our data suggest that injected MSCs were retained within the inflamed glands, could become activated and subsequently recruited leucocytes to the sites of tissue damage.
基金grant from any funding agency,commercial or not-for-profi t sectors
文摘INTRODUCTION Organic material （e.g. nuts in children and bones or food in adults） is the most common foreign body inhaled by patients. Just one tenth of all foreign bodies in the airway are located in the larynx.Laryngeal foreign bodies among adults are rarely seen but con be a life threatening event requiring immediate lifesaving intervention. Here, we report an unusual case of a 56-year-old male patient presenting with sudden dyspnea due to a fulminant onset of massive laryngeal swelling. After securing the airway by tracheostomy, an organic foreign body （a fragment of the patient＇s own teeth） was successfully removed by direct laryngoscopy under general anesthesia.
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.
基金support from the Open Access Publication Fund of the University of Duisburg-Essensupported by the Deutsche Forschungsgemeinschaft(DFG/JA-2461/7-1)+1 种基金CRC TRR332 project A05 to JJthe Stiftung Tumorforschung Kopf-Hals to CK.
文摘Neutrophils have emerged as key players in tumor progression and are often associated with poor prognosis.Despite ongoing efforts to target neutrophil functions in cancer,therapeutic success has been limited.In this study,we addressed the possibility of blocking STAT3 signaling in neutrophils as a targeted therapeutic intervention in cancer.Conditional deletion of Stat3 in a neutrophil-specific manner(Ly6GcreStat3fl/fl mice)significantly impaired tumor growth and metastasis in mice.Neutrophils isolated from these mice exhibited a strong antitumoral phenotype,with increased MHCII,CD80/86 and ICAM-1 expression.Immune profiling of tumors and tumor-draining lymph nodes of these mice revealed significant enrichment of CD8^(+)T cells(granzymeB^(hi),perforin^(hi) and IFN-γ^(hi))with strong cytotoxic activity.To further translate these findings to human settings,we blocked STAT3 signaling in cancer patient neutrophils via the small molecule in^(hi)bitor LLL12 and assessed its effects on patient-derived tumor explants.In agreement with the in vivo mouse data,we observed the expansion and activation of cytotoxic CD8^(+)T cells in such explants.To test the therapeutic applicability of STAT3 targeting,we utilized myeloid cell-selective STAT3 antisense oligonucleotide(CpG-STAT3ASO)to target neutrophils in vivo in tumor-bearing mice.Consistent with previous results,neutrophil-specific STAT3 knockdown impaired tumor growth and enhanced cytotoxic T cell activity in the tumors and tumor-draining lymph nodes of treated mice.These findings highlight STAT3 signaling as a deleterious pathway supporting the protumoral activity of neutrophils and suggest that neutrophil-targeted STAT3 in^(hi)bition is a promising opportunity for cancer immunotherapy,providing novel insights into targeted therapeutic avenues.
