Neutrophils are expanded and abundant in cancer-bearing hosts. Under the influence of CXCR1 and CXCR2 chemokine receptor agonists and other chemotactic factors produced by tumors, neutrophils, and ...granulocytic myeloid-derived suppressor cells (MDSCs) from cancer patients extrude their neutrophil extracellular traps (NETs). In our hands, CXCR1 and CXCR2 agonists proved to be the major mediators of cancer-promoted NETosis. NETs wrap and coat tumor cells and shield them from cytotoxicity, as mediated by CD8+ T cells and natural killer (NK) cells, by obstructing contact between immune cells and the surrounding target cells. Tumor cells protected from cytotoxicity by NETs underlie successful cancer metastases in mice and the immunotherapeutic synergy of protein arginine deiminase 4 (PAD4) inhibitors, which curtail NETosis with immune checkpoint inhibitors. Intravital microscopy provides evidence of neutrophil NETs interfering cytolytic cytotoxic T lymphocytes (CTLs) and NK cell contacts with tumor cells.
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•Tumor-secreted CXCR1 and CXCR2 ligands induce extrusion of NETs•NETs protect tumor cells from CTL and NK cytotoxicity in 3D cultures•Inhibition of NETosis sensitizes tumors to PD-1+CTLA-4 dual checkpoint blockade•NETs impair contact of immune cytotoxic cells with tumor cells in living mice
Extrusion of neutrophil extracellular traps (NETs) constitutes an adhesive mechanism employed by polymorphonuclear leukocytes in microbial defense and plays a role in cancer metastasis. Teijeira et al. show that intratumoral NETs protect malignant cells against cytotoxic attacks of the immune system, such as those elicited by checkpoint-based immunotherapy.
Interleukin-8 (IL8) is a chemokine produced by malignant cells of multiple cancer types. It exerts various functions in shaping protumoral vascularization and inflammation/immunity. We evaluated ...sequential levels of serum IL8 in preclinical tumor models and in patients to assess its ability to estimate tumor burden.
IL8 levels were monitored by sandwich ELISAs in cultured tumor cells supernatants, tumor-xenografted mice serum, and in samples from 126 patients with cancer. We correlated IL8 serum levels with baseline tumor burden and with treatment-induced changes in tumor burden, as well as with prognosis.
IL8 concentrations correlated with the number of IL8-producing tumor cells in culture. In xenografted neoplasms, IL8 serum levels rapidly dropped after surgical excision, indicating an accurate correlation with tumor burden. In patients with melanoma (n = 16), renal cell carcinoma (RCC; n = 23), non-small cell lung cancer (NSCLC; n = 21), or hepatocellular carcinoma (HCC; n = 30), serum IL8 concentrations correlated with tumor burden and stage, survival (melanoma, n = 16; RCC, n = 23; HCC, n = 33), and objective responses to therapy, including those to BRAF inhibitors (melanoma, n = 16) and immunomodulatory monoclonal antibodies (melanoma, n = 8). IL8 concentrations in urine (n = 18) were mainly elevated in tumors with direct contact with the urinary tract.
IL8 levels correlate with tumor burden in preclinical models and in patients with cancer. IL8 is a potentially useful biomarker to monitor changes in tumor burden following anticancer therapy, and has prognostic significance.
Single nucleotide polymorphisms (SNPs) may modulate individual susceptibility to carcinogens. We designed a genome‐wide association study to characterize individuals presenting extreme phenotypes of ...high and low risk to develop tobacco‐induced non‐small cell lung cancer (NSCLC), and we validated our results. We hypothesized that this strategy would enrich the frequencies of the alleles that contribute to the observed traits. We genotyped 2.37 million SNPs in 95 extreme phenotype individuals, that is: heavy smokers that either developed NSCLC at an early age (extreme cases); or did not present NSCLC at an advanced age (extreme controls), selected from a discovery set (n = 3631). We validated significant SNPs in 133 additional subjects with extreme phenotypes selected from databases including >39,000 individuals. Two SNPs were validated: rs12660420 (pcombined = 5.66 × 10−5; ORcombined = 2.80), mapping to a noncoding transcript exon of PDE10A; and rs6835978 (pcombined = 1.02 × 10−4; ORcombined = 2.57), an intronic variant in ATP10D. We assessed the relevance of both proteins in early‐stage NSCLC. PDE10A and ATP10DmRNA expressions correlated with survival in 821 stage I–II NSCLC patients (p = 0.01 and p < 0.0001). PDE10A protein expression correlated with survival in 149 patients with stage I–II NSCLC (p = 0.002). In conclusion, we validated two variants associated with extreme phenotypes of high and low risk of developing tobacco‐induced NSCLC. Our findings may allow to identify individuals presenting high and low risk to develop tobacco‐induced NSCLC and to characterize molecular mechanisms of carcinogenesis and resistance to develop NSCLC.
We report, to our knowledge, the first genomic characterization of individuals presenting extreme phenotypes of risk to develop tobacco‐induced NSCLC. Our results suggest that individuals presenting extreme phenotypes of high and low risk to develop tobacco‐induced NSCLC may present specific genotypes which may be relevant to identify populations at high and low risk of developing NSCLC induced by tobacco and to characterize the underlying molecular mechanisms.
In humans, IL‐8 (CXCL8) is a key chemokine for chemotaxis of polymorphonuclear leukocytes and monocytes/macrophages when acting on CXCR1 and CXCR2. CXCL8 activity on neutrophils includes chemotaxis ...and eliciting the extrusion of neutrophil extracellular traps (NETs). In this study, we show that concentrations of IL‐8 that induce NETosis surpass in at least one order of magnitude those required to elicit chemoattraction in human neutrophils. IL‐8‐induced NETosis was less dependent on G‐proteins than migration, while extracellular Ca+2 chelation similarly inhibited both processes. Reactive oxygen species (ROS) were more important for NETosis than for chemotaxis as evidenced by neutralization with N‐acetyl ‐cysteine. Interestingly, selective blockade with anti‐CXCR1 mAb inhibited NETosis much more readily than chemotaxis, while pharmacological inhibition of both CXCR1 and CXCR2, or selective inhibition for CXCR2 alone, similarly inhibited both functions. Together, these results propose a model according to which low concentrations of IL‐8 in a gradient attract neutrophils to the inflammatory foci, while high receptor‐saturating concentrations of IL‐8 give rise to NETosis once leukocytes reach the core of the inflammatory insult.
Interleukin‐8 can induce chemotaxis and NETosis in human peripheral blood neutrophils. This paper shows that at low concentrations, IL‐8 preferentially induces chemotaxis while NETosis is mainly promoted at high IL‐8 concentrations. IL‐8 induced NETosis and chemotaxis have different receptor and signaling requirements.
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Background: Tobacco is the main risk factor for developing lung cancer. Yet, while some heavy smokers develop lung cancer at young age others never develop it, even at advanced age. This ...suggests a remarkable variability in the individual susceptibility to the carcinogenic effects of tobacco. We characterized the germline profile of subjects presenting these extreme phenotypes with Whole Exome Sequencing (WES) and Machine Learning (ML). Methods: We sequenced germline DNA from heavy smokers who either developed lung adenocarcinoma at early age ( extreme cases) or did not develop it at advanced age ( extreme controls). The discovery and validation cohorts included respectively 50 and 66 extreme cases and 50 and 83 extreme controls, selected from databases including > 6,000 subjects. We selected individual coding variants and variant-rich genes showing a significantly different distribution between extreme cases and controls. We trained ML models (Logistic Regression, Random Forest, Support Vector machine Classifier (SVC)) on the discovery cohort to classify subjects into their respective phenotypes and tested them on the validation cohort. Results: Mean age for extreme cases and controls in both cohorts was 50.2 and 78.4 years. Mean tobacco consumption was 38.1 and 59.1 pack-years. We validated 16 significant individual variants. The most significant variants were in ADAMTS7 (2 variants) in cases and TMEM191B (1) in controls. We validated 33 genes enriched with significant variants. The genes harboring more variants were HLA-A (4 variants) and ADAMTS7 (2) in cases; and PLIN4 (2) in controls (Table). We trained several ML models on the discovery cohort using as input the 16 significant individual variants and the number of variants in the 33 enriched genes. We tested them in the validation cohort obtaining accuracy of 72% and AUC-ROC of 87.4% with the best model (SVC), using 16 variants as input, confirming their association with the phenotypes. Functions of validated genes included oncogenes, tumor-suppressors, DNA repair, maintenance of genomic stability, HLA mediated antigen presentation and regulation of proliferation, migration, apoptosis and inflammatory pathways. Conclusions: Individuals presenting phenotypes of extreme high and low risk of developing tobacco-induced lung adenocarcinoma have different germline profiles. Our strategy may allow to identify high-risk subjects and to develop new therapeutic approaches. Table: see text
To investigate whether the timing of a previous hospital admission for acute heart failure (AHF) is a prognostic factor for AHF patients revisiting the emergency department (ED) in the subsequent ...12-month follow-up. All ED AHF patients enrolled in the previously described EAHFE registry were stratified by the presence or absence of an AHF hospitalization admission in the prior 12 months. The primary outcome was 12-month all-cause mortality post ED visit. Secondary end points were hospital admission, prolonged hospitalization (> 7 days), mortality during hospitalization and a 90-day post-discharge adverse composite event (ACE) rate, defined as ED revisits due to AHF, hospitalizations due to AHF, or all-cause mortality. Outcomes were adjusted for baseline and AHF episode characteristics.Of 5,757 patients included, the median age was 84 years (IQR 77–88); 57% were women, and 3,759 (65.3%) had an AHF hospitalization in the previous 12 months. The 12-month mortality was 37% (41.7% vs. 28.3%
p
< 0.001), hospital admission was 76.1% (78.8% vs. 71.1%
p
< 0.001) ACE was 60.2% (65.1% vs. 50.5%
p
< 0.001). In the adjusted analysis, patients with AHF hospitalization in the prior 12 months had a higher mortality (HR = 1.41; 95% CI 1.27–1.56), 90-day ACE rate (HR = 1.45: 95% CI 1.32–1.59), and more hospital admissions (OR = 1.32; 95% CI 1.16–1.51), with shorter times since the previous hospitalization being related to the outcomes analyzed. One-year mortality, adverse events at 90 days, and readmission rates are increased in ED AHF patients previously admitted within the last 12 months.
The authors sought to evaluate clinical outcomes of patients after an episode of acute heart failure (AHF) according to their adherence to the Mediterranean diet (MedDiet).
It has been proved that ...MedDiet is a useful tool in primary prevention of cardiovascular diseases. However, it is unknown whether adherence to MedDiet is associated with better outcomes in patients who have already experienced an episode of AHF.
We designed a prospective study that included consecutive patients diagnosed with AHF in 7 Spanish emergency departments (EDs). Patients were included if they or their relatives were able to answer a 14-point score of adherence to the MedDiet, which classified patients as adherents (≥9 points) or nonadherents (≤8 points). The primary endpoint was all-cause mortality at the end of follow-up, and secondary endpoints were 1-year ED revisit without hospitalization, rehospitalization, death, and a combined endpoint of all these variables for patients discharged after the index episode. Unadjusted and adjusted hazard ratios (HRs) were calculated.
We included 991 patients (mean age of 80 ± 10 years, 57.8% women); 523 (52.9%) of whom were adherent to the MedDiet. After a mean follow-up period of 2.1 ± 1.3 years, no differences were observed in survival between adherent and nonadherent patients (HR of adherents HR
= 0.86; 95% confidence interval CI: 0.73 to 1.02). The 1-year cumulative ED revisit for the whole cohort was 24.5% (HR
= 1.10; 95% CI: 0.84 to 1.42), hospitalization 43.7% (HR
= 0.74; 95% CI: 0.61 to 0.90), death 22.7% (HR
= 1.05; 95% CI: 0.8 to 1.38), and combined endpoint 66.8% (HR
= 0.89; 95% CI: 0.76 to 1.04). Adjustment by age, hypertension, peripheral arterial disease, previous episodes of AHF, treatment with statins, air-room pulsioxymetry, and need for ventilation support in the ED rendered similar results, with no statistically significant differences in mortality (HR
= 0.94; 95% CI: 0.80 to 1.13) and persistence of lower 1-year hospitalization for adherents (HR
= 0.76; 95% CI: 0.62 to 0.93).
Adherence to the MedDiet did not influence long-term mortality after an episode of AHF, but it was associated with decreased rates of rehospitalization during the next year.
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