Pancreatic melatonin enhances anti-tumor immunity in pancreatic adenocarcinoma through regulating tumor-associated neutrophils infiltration and NETosis

Tumor microenvironment contributes to poor prognosis of pancreatic adenocarcinoma (PAAD) patients. Proper regulation could improve survival. Melatonin is an endogenous hormone that delivers multiple bioactivities. Here we showed that pancreatic melatonin level is associated with patients' survival. In PAAD mice models, melatonin supplementation suppressed tumor growth, while blockade of melatonin pathway exacerbated tumor progression. This anti-tumor effect was independent of cytotoxicity but associated with tumor-associated neutrophils (TANs), and TANs depletion reversed effects of melatonin. Melatonin induced TANs infiltration and activation, therefore induced cell apoptosis of PAAD cells. Cytokine arrays revealed that melatonin had minimal impact on neutrophils but induced secretion of Cxcl2 from tumor cells. Knockdown of Cxcl2 in tumor cells abolished neutrophil migration and activation. Melatonin-induced neutrophils presented an N1-like anti-tumor phenotype, with increased neutrophil extracellular traps (NETs) causing tumor cell apoptosis through cell-to-cell contact. Proteomics analysis revealed that this reactive oxygen species (ROS)-mediated inhibition was fueled by fatty acid oxidation (FAO) in neutrophils, while FAO inhibitor abolished the anti-tumor effect. Analysis of PAAD patient specimens revealed that CXCL2 expression was associated with neutrophil infiltration. CXCL2, or TANs, combined with NET marker, can better predict patients' prognosis. Collectively, we discovered an anti-tumor mechanism of melatonin through recruiting N1-neutrophils and beneficial NET formation.

Emerging nanomedicine-based therapeutics for hematogenous metastatic cascade inhibition: Interfering with the crosstalk between "seed and soil"

Despite considerable progresses in cancer treatment, tumor metastasis is still a thorny issue, which leads to majority of cancer-related deaths. In hematogenous metastasis, the concept of "seed and soil" suggests that the crosstalk between cancer cells (seeds) and premetastatic niche (soil) facilitates tumor metastasis. Considerable efforts have been dedicated to inhibit the tumor metastatic cascade, which is a highly complicated process involving various pathways and biological events. Nonetheless, satisfactory therapeutic outcomes are rarely observed, since it is a great challenge to thwart this multi-phase process. Recent advances in nanotechnology-based drug delivery systems have shown great potential in the field of anti-metastasis, especially compared with conventional treatment methods, which are limited by serious side effects and poor efficacy. In this review, we summarized various factors involved in each phase of the metastatic cascade ranging from the metastasis initiation to colonization. Then we reviewed current approaches of targeting these factors to stifle the metastatic cascade, including modulating primary tumor microenvironment, targeting circulating tumor cells, regulating premetastatic niche and eliminating established metastasis. Additionally, we highlighted the multi-phase targeted drug delivery systems, which hold a better chance to inhibit metastasis. Besides, we demonstrated the limitation and future perspectives of nanomedicine-based anti-metastasis strategies.

Safety and immunogenicity of seasonal inactivated influenza vaccine (split virion) and cross-reactive antibody responses to the H7N9 avian influenza virus / 中华流行病学杂志

<p><b>OBJECTIVE</b>To evaluate the safety and immunogenicity of seasonal inactivated influenza vaccine (split virion) and to analyze its cross-reactive antibody responses to H7N9 avian influenza virus.</p><p><b>METHODS</b>An open-labeled clinical trial was carried out in infants aged 6-35 months, adults aged 18-60 years and the elderly aged >60 years. After vaccinations (one dose for adults and the elderly and two doses for infants), adverse events were observed. Serum samples were obtained before vaccination and 21 days after vaccination from adults and elderly subjects. Three types of antibody against seasonal influenza virus and antibody against H7N9 avian influenza virus were tested using microhemagglutination inhibition (HI) assay. Immunogenicity of the vaccine was evaluated based on the immunogenicity criteria for adults and the elderly, set by the Committee for Medicinal Products for Human Use (CHMP) for the European Medicines Agency.</p><p><b>RESULTS</b>A total of 202 subjects (65 infants, 69 adults and 68 elderly) were enrolled and injected for at least one dose. The overall rate of adverse events was 12.4% (25/202) and most of them were under systemic reaction. No serious adverse event was reported. Pre- and post-vaccination serum samples were collected from 124 subjects (64 adults, 60 elderly). After 21 days of vaccination, the sero-conversion rate, sero-protection rate, and geometric mean titer (GMT) ratio (post-/pre-vaccination) of antibody against seasonal influenza virus were 78.1%-90.6%, 92.2%-100.0% and 7.9-41.0 among adults while 66.7%-83.3%, 86.7%-100.0% and 5.7-20.4 among the elderly, respectively. However, after vaccination, both sero-conversion rate and sero-protection rate of antibody against H7N9 avian influenza virus among adults and the elderly became zero, with GMT ratio between 1.2 and 1.4.</p><p><b>CONCLUSION</b>This trial vaccine appeared to have good safety and immunogenicity but inducing no cross-reactive antibody response to H7N9 avian influenza virus.</p>