interleukin-8 and Lymphoma--Large-B-Cell--Diffuse

Systemic anaplastic large-cell lymphoma (ALCL) in human immunodeficiency virus (HIV)-infected individuals showing an extensive infiltrate of neutrophils has been reported and referred to as 'neutrophil-rich' CD30+ ALCL. Secondary cutaneous involvement has been found in a subset of these cases. We report the clinicopathological features of four immunocompetent patients with primary cutaneous neutrophil-rich ALCL and present a new histological subtype with a dissolute growth pattern of CD30+ tumour cells. Four HIV-negative patients presented with rapidly growing solitary or multiple tumours located on the face. Ulceration of the lesions with purulent discharge was a typical finding. Various inflammatory dermatoses were considered clinically in all cases. The histological hallmark was a large number of neutrophils in the infiltrate that masked neoplastic CD30+ anaplastic cells. In two cases, a dissolute growth pattern of anaplastic tumour cells was observed. In two cases, a strong correlation between tumour growth and interleukin (IL)-8 cytokine pattern as well as the production of IL-8 by tumour cells was demonstrated. The diagnosis of neutrophil-rich ALCL is challenging clinically and histologically as the tumour cell compartment is masked by an extensive inflammatory infiltrate of neutrophils and other reactive cells such as histiocytes which may be mainly due to release of IL-8 by tumour cells. The term 'pyogenic' designates the typical feature of this distinct neutrophil-rich ALCL, namely abscess formation ('pyo-') by cytokines (IL-8) produced by tumour cells ('-genic'). The clinical behaviour of this type is the same as in primary cutaneous CD30+ ALCL with classical histological presentation.

Topics: Abscess; Adult; Facial Neoplasms; Female; Humans; Interleukin-8; Ki-1 Antigen; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Neutrophils; Skin Neoplasms; Tumor Cells, Cultured

CXCL chemokines (CXCLs) are small cytokines or signal proteins secreted by cells that have been proven to be linked to the occurrence and development of many kinds of cancer. However, the expression and diagnostic and prognostic value of CXCLs in diffuse large B-cell lymphoma (DLBCL) remain to be further studied. We obtained CXCL transcription and survival data of patients with DLBCL from Oncomine, Gene Expression Profiling Interactive Analysis (GEPIA), The Cancer Genome Atlas (TCGA), TIMER and cBioPortal databases. R software, STRING and EXCEL were used to process the data. This study discovered that the expression levels of CXCL9-14 in DLBCL were higher than those in normal tissues, while CXCL4, CXCL7 and CXCL8 were lower in tumor than in normal tissues. The expression levels of CXCL2, CXCL10 and CXCL11 were related to tumor stage. CXCL9-14 could be used as an auxiliary molecular marker for the diagnosis of DLBCL. CXCL17 might be a potential prognostic marker of DLBCL.

Topics: beta-Thromboglobulin; Biomarkers, Tumor; Chemokine CXCL10; Chemokine CXCL11; Chemokine CXCL2; Chemokine CXCL9; Chemokines, CXC; Disease-Free Survival; Female; Gene Expression Regulation, Neoplastic; Humans; Interleukin-8; Lymphoma, Large B-Cell, Diffuse; Male; Platelet Factor 4; Prognosis; Tumor Microenvironment

The efficacy and side effects of the second-time humanized CD19 chimeric antigen receptor (CD19-CAR) T-cell therapy after unsuccessful first-time anti-CD19-CAR T-cell therapy and subsequent ibrutinib salvage treatment were observed in patients with refractory B-cell lymphoma. In our study, 3 patients with refractory mantle cell lymphoma (MCL) and 4 patients with refractory follicular lymphoma (FL) reached stable disease (SD), partial remission (PR), or progression of disease (PD) after first-time humanized anti-CD19-CAR T-cell therapy. They received ibrutinib as a salvage treatment and kept an SD in the following 7-16 mo, but their disease progressed again during ibrutinib salvage treatment. All 7 patients received a second-time humanized anti-CD19-CAR T-cell therapy, which was the same as their first-time anti-CD19-CAR T-cell therapy. In total, 3 MCL patients and 3 FL patients reached complete response (CR) with the second-time anti-CD19-CAR T-cell therapy combined with ibrutinib, whereas 1 FL patient reached PR. There were no differences in the transduction efficiency and proliferation between the 2 instances of anti-CD19-CAR T-cell therapy. However, the second-time anti-CD19-CAR T-cell therapy led to higher peaks of anti-CD19-CAR T cells and anti-CD19-CAR gene copies, but also to higher grades of cytokine release syndrome (CRS) and more serious hematological toxicity. The successful outcome of the second-time anti-CD19-CAR T-cell therapy might suggest that the previous ibrutinib treatment improved the activities of anti-CD19-CAR T cells.

Topics: Adenine; Adult; Aged; Combined Modality Therapy; Disease Progression; Drug Resistance, Neoplasm; Female; Humans; Immunotherapy, Adoptive; Interleukin-6; Interleukin-8; Lymphoma, B-Cell; Lymphoma, Follicular; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Mantle-Cell; Male; Middle Aged; Piperidines; Receptors, Chimeric Antigen; Receptors, Interleukin-2; Remission Induction; Retreatment; Salvage Therapy; Treatment Outcome

More than 30% of patients with diffuse large B-cell lymphoma (DLBCL) experience treatment failure after first-line therapy. Neutrophil extracellular traps (NETs), a pathogen-trapping structure in tumor microenvironment, can promote the transition of autoimmunity to lymphomagenesis. Here, we investigate whether NETs play a novel role in DLBCL progression and its underlying mechanism.. Higher levels of NETs in plasma and tumor tissues were associated with dismal outcome in patients with DLBCL. Furthermore, we identified NETs increased cell proliferation and migration. Our data reveal a tumor-NETs aggressive interaction in DLBCL and indicate that NETs is a useful prognostic biomarker and targeting this novel cross-talk represents a new therapeutic opportunity in this challenging disease.

Topics: Adult; Aged; Aged, 80 and over; Animals; Autoimmunity; Cell Line, Tumor; Disease Models, Animal; Disease Progression; Extracellular Traps; Female; Humans; Interleukin-8; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Neutrophils; Progression-Free Survival; Receptors, Interleukin-8B; Signal Transduction; Toll-Like Receptor 9; Tumor Microenvironment; Young Adult

Tumor-infiltrating neutrophils have been implicated in malignant development and progression, but mechanisms are ill defined. Neutrophils produce a proliferation-inducing ligand APRIL/TNFSF13, a factor that promotes development of tumors from diverse origins, including diffuse large B-cell lymphoma (DLBCL). High APRIL expression in DLBCL correlates with reduced patient survival, but the pathway(s) dictating APRIL expression are not known. Here, we show that all blood neutrophils constitutively secrete APRIL, and inflammation-associated stimuli, such as TNF, further upregulate APRIL. In a significant fraction of DLBCL patients, tumor cells constitutively produced the ELC-CXC chemokine CXCL-8 (IL8), enabling them to recruit APRIL-producing blood neutrophils. CXCL-8 production in DLBCL was unrelated to the cell of origin, as APRIL-producing neutrophils infiltrated CXCL-8

Topics: Animals; Humans; Interleukin-8; Ligands; Lymphoma, Large B-Cell, Diffuse; Mice; Neutrophils; Tumor Microenvironment; Tumor Necrosis Factor Ligand Superfamily Member 13

Both tumor-associated neutrophils (TAN) and cancer-associated fibroblasts (CAFs) display specific phenotypic and functional features and contribute to tumor cell niche. However, their bidirectional crosstalk has been poorly studied, in particular in the context of hematological malignancies. Follicular lymphomas (FL) and diffuse large B-cell lymphomas (DLBCL) are two germinal center-derived lymphomas where various cell components of infiltrating microenvironment, including TAN and CAFs, have been demonstrated to favor directly and indirectly malignant B-cell survival, growth, and drug resistance. We show here that, besides a direct and contact-dependent supportive effect of neutrophils on DLBCL B-cell survival, mediated through the BAFF/APRIL pathway, neutrophils and stromal cells cooperate to sustain FL B-cell growth. This cooperation relies on an overexpression of IL-8 by lymphoma-infiltrating stromal cells that could thereafter efficiently promote neutrophil survival and prime them to neutrophil extracellular trap. Conversely, neutrophils are able to activate stromal cells in a NF-κB-dependent manner, inducing their commitment towards an inflammatory lymphoid stroma phenotype associated with an increased capacity to trigger malignant B-cell survival, and to recruit additional monocytes and neutrophils through the release of CCL2 and IL-8, respectively. Altogether, a better understanding of the lymphoma-supporting effects of neutrophils could be helpful to design new anti-tumor therapeutic strategies.

Topics: Adult; Apoptosis; B-Cell Activating Factor; B-Lymphocytes; Cell Differentiation; Cell Movement; Cell Survival; Chemokine CCL2; Child; Extracellular Traps; Fibroblasts; Germinal Center; Humans; I-kappa B Kinase; Interleukin-8; Lymphoma, Follicular; Lymphoma, Large B-Cell, Diffuse; Neutrophil Infiltration; Neutrophils; NF-kappa B; Receptors, Tumor Necrosis Factor, Type I; Stromal Cells; Tumor Cells, Cultured; Tumor Microenvironment

Cytokines play important roles in the pathogenesis of lymphomas. This study aimed to determine the relationship(s) between serum levels of interleukin (IL)-6, IL-8 and IL-10, measured by enzyme-immunoassay, and the clinical characteristics and outcomes in 46 untreated patients with diffuse large B-cell lymphoma (DLBCL). Serum IL-6, IL-8 and IL-10 levels were higher in DLBCL patients than in control subjects. Elevated levels of IL-6, IL-8 and IL-10 correlated with more adverse disease features. Consequently, patients with elevated IL-6, IL-8 and IL-10 levels prior to treatment had a lower response to therapy. Furthermore, those with elevated IL-6 and IL-10 levels had poor median, 3-year and 5-year survival, while elevated serum IL-8 level did not correlate with overall survival. Worse survival was also confirmed in patients with combined elevated pretreatment serum levels of IL-6, IL-8 and IL-10 (none, one, two or three elevated). Multivariate analysis identified elevated values of IL-6 and IL-10 and response to therapy as significant predictors for overall survival. Serum levels of IL-6, IL-8 and IL-10 before treatment of patients with newly diagnosed DLBCL may give some insight into the possible prognosis and thus facilitate the decisions regarding therapeutic approaches for individual patients.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Case-Control Studies; Female; Humans; Interleukin-10; Interleukin-6; Interleukin-8; Kaplan-Meier Estimate; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Neoplasm Staging; Prognosis; Proportional Hazards Models; Risk

We here present the case of a 5-yr-old girl with pyoderma gangrenosum (PG) in association with underlying CD30+ anaplastic large cell lymphoma with increased serum cytokine levels (interleukin-8, granulocyte colony-stimulating factor). An association between PG and increased cytokine levels was suggested. Even in children, dermatosis of PG should receive prompt careful evaluation for underlying hematological malignancy.

Topics: Child, Preschool; Cytokines; Female; Granulocyte Colony-Stimulating Factor; Humans; Interleukin-8; Ki-1 Antigen; Lymphoma, Large B-Cell, Diffuse; Osteolysis; Pyoderma Gangrenosum

A 43-year-old female with large T-cell non-Hodgkin's lymphoma and central nervous system (CNS) involvement underwent HLA-identical-sibling peripheral blood stem cell transplantation (SCT) during her third complete remission. She presented a possible refractory CNS relapse 5 months after the transplant. She was then treated with intrathecal (IT) donor lymphocyte infusions (DLI). No side effects were observed after three DLI injections. The patient died 13 months later from infectious complications with no evidence of progressive disease. To our knowledge, this is the first case report of IT DLI for possible refractory lymphomatous meningitis.

Topics: Adult; Disease Progression; Female; HLA Antigens; Humans; Injections, Spinal; Interleukin-6; Interleukin-8; Lymphocyte Transfusion; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Magnetic Resonance Imaging; Meningitis; Remission Induction; Stem Cell Transplantation

Induction of chemokine gene expression from peripheral blood mononuclear cells (PBMCs) stimulated by proinflammatory cytokines plays an important role in both wound repair and response to infectious agents. In the present study, we show that the proinflammatory cytokine interleukin-6 (IL-6) potently induced mRNA expression and secretion of the CC chemokine monocyte chemotactic protein 1 (MCP-1) in PBMCs. In addition, because human immunodeficiency virus (HIV) infection in vivo and in vitro has been shown to dysregulate the production of and/or the response to cytokines, PBMCs from both healthy uninfected and HIV-infected individuals were studied for their constitutive and IL-6-induced expression of MCP-1. No substantial differences were observed between the two groups of individuals. In addition, IL-6 upregulated MCP-1 expression in the promonocytic cell line U937 and in its chronically HIV-infected counterpart, U1. In these cell lines, IL-6 selectively induced MCP-1 and not other chemokines, including regulated upon activation normal T cells expressed and secreted (RANTES), macrophage inflammatory protein-1alpha (MIP-1alpha), MIP-1beta, and IL-8. IL-6 induction of MCP-1 was partially inhibited by hydrocortisone in U1 cells. Thus, IL-6 activates PBMCs to secrete MCP-1, a CC chemokine pivotal for monocyte recruitment in tissue and organs in which important inflammatory events occur.

Topics: Anti-Inflammatory Agents; Cells, Cultured; Chemokine CCL2; Chemokine CCL3; Chemokine CCL4; Chemokine CCL5; Gene Expression Regulation; Gene Expression Regulation, Leukemic; HIV Infections; Humans; Hydrocortisone; Interferon-gamma; Interleukin-6; Interleukin-8; Leukocytes, Mononuclear; Lymphoma, Large B-Cell, Diffuse; Macrophage Inflammatory Proteins; Monocytes; Neoplasm Proteins; Neoplastic Stem Cells; RNA, Messenger; RNA, Neoplasm; Tetradecanoylphorbol Acetate; Tumor Cells, Cultured

FCE 27266, 2,2,'-(carbonyl-bis(imino-N-methyl-4,2-pyrrole carbonyl-imino¿N-methyl-4,2-pyrrole¿carbonylimino])-bis- (1,5-naphthalene) disulfonic acid, is a noncytotoxic compound able to complex bFGF, PDGF beta, IL-8, VEGF and IL-1 beta and to inhibit the binding to their receptors. A single intravenous treatment 48 h prior to intravenous injection with tumor cells was associated with 60% inhibition of lung metastasis from B16F10 murine melanoma and 82% inhibition of liver metastasis from M5076 murine reticulosarcoma. Marginal inhibition was observed in the latter model, administering the drug 24 h after tumor cell injection. Efficacy was maintained in athymic mice, with 95 and 100% inhibition of lung metastasis from B16F10 melanoma and A375 human melanoma. The antimetastatic activity was confirmed in two models of spontaneous metastasis: in Lewis lung carcinoma implanted intramuscularly, daily intraperitoneal treatment from day 1 to 17 was associated with 77% inhibition of lung metastasis; on M5076 reticulosarcoma implanted intramuscularly, daily intraperitoneal treatment from day 1 to 14 prior to amputation of the tumor was associated with significant inhibition of liver metastasis (79%); conversely, daily intraperitoneal treatment from day 15 to 28 starting 1 day after amputation was marginally effective. The administered doses did not inhibit the growth of the primary tumor in both models. It is concluded that FCE 27266 is a novel, promising molecule, with significant efficacy on lung and liver metastases of murine and human origin; its mode of action is still under study and is probably exerted through inhibition of growth factors and cytokines influencing the different steps of angiogenesis and metastasis.

Topics: 3T3 Cells; Animals; Antineoplastic Agents; Binding, Competitive; Cell Line; Distamycins; Endothelial Growth Factors; Female; Fibroblast Growth Factor 2; HL-60 Cells; Humans; Interleukin-1; Interleukin-8; Kinetics; Liver Neoplasms; Lung Neoplasms; Lymphokines; Lymphoma, Large B-Cell, Diffuse; Male; Melanoma; Melanoma, Experimental; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Nude; Neoplasm Metastasis; Platelet-Derived Growth Factor; Receptors, Growth Factor; Transplantation, Heterologous; Tumor Cells, Cultured; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

A quantitative polymerase chain reaction (PCR) assay for mRNA expression of interleukin-8 (IL-8), a neutrophil chemotactant and activator, was developed to examine the expression of this cytokine by colonic mucosa. A synthetic IL-8 RNA deleted in size of native IL-8 mRNA was used as an external control. The synthetic IL-8 RNA was mixed with total RNA from cells and converted to cDNA and amplified by PCR simultaneously. The lower limit of sensitivity for the assay was found to be more than 1 femtogram of IL-8 mRNA. The assay determined IL-8 mRNA expression when the RNA was isolated from either human histiocytic lymphoma cell line U937 cells or human colonic mucosa obtained from colitis patients and healthy controls. The development of the rapid and sensitive assay should provide a means to more fully evaluate the role of this cytokine in diverse disease states with small scale.

Topics: Base Sequence; Colitis, Ulcerative; DNA Primers; Electrophoresis, Agar Gel; Humans; Interleukin-8; Intestinal Mucosa; Lymphoma, Large B-Cell, Diffuse; Molecular Sequence Data; Polymerase Chain Reaction; RNA, Messenger; Tumor Cells, Cultured