The immune component of the tumor microenvironment is essential for the regulation of cancer progression. In breast cancer (BC), a patient’s tumor mass is frequently infiltrated by neutrophils (tumor-associated neutrophils, TANs). Our study addressed the role of TANs and their mechanism of action in BC. Using quantitative IHC, ROC, and Cox analysis, we demonstrated that a high density of TANs infiltrating the tumor parenchyma was predictive of poor prognosis and of decreased progression-free survival of patients with BC, who underwent surgical tumor removal without previous neoadjuvant chemotherapy, in three different cohorts: training, validation, and independent cohorts. Conditioned medium from human BC cell lines prolonged the life span of healthy donor neutrophils ex vivo. Neutrophils activated by the supernatants of BC lines demonstrated an increased ability to stimulate proliferation, migration, and invasive activity of BC cells. Cytokines involved in this process were identified using antibody arrays. The relationship between these cytokines and the density of TANs was validated by ELISA and IHC in fresh BC surgical samples. It was determined that tumor-derived G-CSF significantly extended the lifespan and increased the metastasis-promoting activities of neutrophils via the PI3K-AKT and NF-κB pathways. Simultaneously, TAN-derived RLN2 promoted the migratory abilities of MCF7cells via PI3K-AKT-MMP-9. Analysis of tumor tissues from 20 patients with BC identified a positive correlation between the density of TANs and the activation of the G-CSF-RLN2-MMP-9 axis. Finally, our data demonstrated that TANs in human BC have detrimental effects, supporting malignant cell invasion and migration.

Chronic lymphocytic leukemia (CLL) is a type of highly heterogeneous mature B-cell malignancy with various disease courses. Although a multitude of prognostic markers in CLL have been reported, insights into the role of super-enhancer (SE)-related risk indicators in the occurrence and development of CLL are still lacking. A super-enhancer (SE) is a cluster of enhancers involved in cell differentiation and tumorigenesis, and is one of the promising therapeutic targets for cancer therapy in recent years. In our study, the CLL-related super-enhancers in the training database were processed by LASSO-penalized Cox regression analysis to screen a nine-gene prognostic model including TCF7, VEGFA, MNT, GMIP, SLAMF1, TNFRSF25, GRWD1, SLC6AC, and LAG3. The SE-related risk score was further constructed and it was found that the predictive performance with overall survival and time-totreatment (TTT) was satisfactory. Moreover, a high correlation was found between the risk score and already known prognostic markers of CLL. In the meantime, we noticed that the expressions of TCF7, GMIP, SLAMF1, TNFRSF25, and LAG3 in CLL were different from those of healthy donors (p < 0.01). Moreover, the risk score and LAG3 level of matched pairs before and after treatment samples varied significantly. Finally, an interactive nomogram consisting of the nine-gene risk group and four clinical traits was established. The inhibitors of mTOR and cyclin-dependent kinases (CDKs) were considered effective in patients in the high-risk group according to the pRRophetic algorithm. Collectively, the SE-associated nine-gene prognostic model developed here may be used to predict the prognosis and assist in the risk stratification and treatment of CLL patients in the future.

Immune component of tumor microenvironment is essential for the regulation of cancer progression. Tumor mass is frequently infiltrated by neutrophils (tumor-associated neutrophils, TANs) in breast cancer (BC) patients. However, the role of TANs and the mechanisms of their action in BC are still unclear. Using quantitative IHC, ROC and Cox analysis, we demonstrate here that high density of TANs infiltrating tumor parenchyma is predictive for poor prognosis and for the decreased progression-free survival of patients with BC that underwent surgical tumor removal without previous neoadjuvant chemotherapy in all 3 cohorts (training cohort, n = 170; validation cohorts, n = 130, independent cohorts, n = 95). Conditioned medium of human breast cancer cell lines prolonged life span of healthy donor neutrophils ex vivo. Neutrophils, activated by supernatants of breast cancer lines, demonstrated the increased ability to stimulate proliferation, migration and invasive activity of breast cancer cells. Cytokines involved in this process have been identified by antibody array. Relationships between these cytokines and density of TANs were validated by ELISA and IHC in fresh breast cancer surgical samples. Identified by antibody arrays, tumor-derived G-CSF significantly prolonged the lifespan and increased the metastasis-promoting activities of neutrophils via PI3K-AKT and NFκB pathway. Simultaneously, TAN-derived RLN2 promoted the migratory abilities of MCF-7 cells via PI3K-AKT-MMP-9. Analysis of tumor tissues from 20 BC patients and RNA-seq from TCGA BC patients identified a positive correlation of density of TANs with the activation of G-CSF-RLN2-MMP-9 axis. Our data indicate that TANs in human breast cancer have detrimental activity supporting malignant cells invasion and migration.

Chronic lymphocytic leukemia (CLL) is a group of highly heterogeneous mature B cell malignancy with various disease courses and diagnoses. Although there is a multitude of prognostic markers in CLL, insights into the role of super-enhancer(SE)-related risk indicators are still lacking. Super-enhancer(SE) is a novel concept drew in recent years which is a cluster of enhancers involved in cell differentiation and tumorigenesis ,and is one of the promising therapeutic targets for cancer therapy. The CLL-related super-enhancers in training database were processed by Lasso penalized Cox regression analysis to screen a nine-gene prognostic model including TCF7, VEGFA, MNT, GMIP, SLAMF1, TNFRSF25, GRWD1, SLC6AC, and LAG3. A SE-related risk score was further constructed and the predictive performance with overall survival and time-to-treatment (TTT) was satisfactory. Besides, a high correlation was found between the risk score and already known prognostic markers of CLL. Meantime, we noticed that the expression of TCF7, GMIP, SLAMF1, TNFRSF25, and LAG3 in CLL were different from healthy donors(P < 0.01), moreover, the risk score and LAG3 level of matched pairs before and after treatment samples varied significantly, although these results were not completely consistent in different datasets. An interactive nomogram consisting of the nine-gene risk group and four clinical traits was established. And the inhibitors of mTOR and cyclin dependent kinases (CDKs) were considered effective in patients of high-risk group according to the pRRophetic algorithm. Therefore, the SE-associated nine-gene prognostic model developed here may be used to predict the prognosis and assist in the risk stratification ,treatment of CLL patients in the future.

Background: Hemophagocytic lymphohistiocytosis (HLH) a hyperinflammation disease and have high early mortality. The neutrophil-lymphocyte ratio (NLR) plays a prognostic role in various inflammation conditions. However, the role of NLR in HLH remains unknown.Results: 92 patients were collected from Sep 2014 to Dec 2019, the median age was 50 years (16-88) and 54 patients (58.6%) were male. 39 patients (42.3%) died during a 30-day follow-up. In addition, NLR was higher in nonsurvivor than survivor (P=0.005), higher NLR was correlated with older age (P=0.020), worse survival status (P=0.006), lower HB level (P=0.008), longer PT level (P=0.010), higher creatinine level (0.027) and higher IL-6 level (P=0.008)and in multivariate analysis, NLR (HR=2.508, 95%CI: 1.275-4.934), was indicated as an independent prognostic factor for early death. Conclusions: NLR was correlated with early death in HLH, suggest NLR could be used as a reference indicator for the monitoring and management of HLH.