| 1. |
- Glimelius, Ingrid, et al.
(författare)
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Angiogenesis and mast cells in Hodgkin lymphoma
- 2005
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Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 0887-6924 .- 1476-5551. ; 19:12, s. 2360-2362
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Tidskriftsartikel (refereegranskat)
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| 2. |
- Glimelius, Ingrid, 1975-
(författare)
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Hodgkin Lymphoma – an Interplay Between Tumour Cell and Microenvironment
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Hodgkin lymphoma (HL) is a malignant disorder characterised by few tumour cells surrounded by a massive infiltrate of inflammatory cells, fibrosis, and microvessels. Therefore, it is a good model in which to study the interplay between tumour cells and the microenvironment. In a population-based series, stage IIB had poor prognosis, equivalent to the most advanced stage (stage IV). The most prominent negative prognostic factor was tumour bulk in the mediastinum (often large fibrotic tumours). The tumour cells expressed interleukin-9 (IL-9) in their cytoplasm in half of the cases. These cases had an over representation of nodular sclerosis histology (characterised by fibrotic bands) and infiltration of eosinophils and mast cells in the tumours. Despite this, IL-9 expression was not a negative prognostic factor. A role of inflammatory cells is to contribute to angiogenesis. Yet, a correlation between high microvessel count and high mast cell number in HL tumours was not identified, in contrast to other lymphomas. However, a correlation to poor prognosis was seen for cases with high microvessel count. Eosinophils contain eosinophil cationic protein (ECP). ECP was cytotoxic to cells from two HL cell lines of B-cell origin and one HL line of T-cell origin. At high concentrations, the cytotoxic effect was not as pronounced for the line of T-cell origin. If the in vitro cell lines are representative of HL in vivo, eosinophils may have different roles in different HL tumours. In addition to the effect from tumour cells, host-related factors contribute to the inflammatory infiltrate in HL. A history of asthma and hives, and carrying the ECP434GG genotype were associated with elevated numbers of eosinophils, whereas, history of tobacco smoking was associated with lower numbers. HL is a complex tumour consisting of recruited and subverted normal cells, fibrosis and angiogenesis: these constitute the microenvironment, which likely supports tumour cell growth, and differs between patients.
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| 3. |
- Glimelius, Ingrid, et al.
(författare)
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IL-9 expression contributes to the cellular composition in Hodgkin lymphoma
- 2006
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Ingår i: European Journal of Haematology. - : Wiley. - 0902-4441 .- 1600-0609. ; 76:4, s. 278-283
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES:The presence of numerous mast cells or eosinophils in Hodgkin lymphoma (HL) tumours have both been described as negative prognostic factors. One cytokine related to HL is interleukin-9 (IL-9) and it is known to affect both mast cells and eosinophils. The aim of this study was to explore if the expression of IL-9 correlates to the presence of these inflammatory cells in HL tumours.METHODS:In 131 HL biopsies, immunostainings for IL-9 and IL-9 receptor (IL-9R) were performed. The same material was previously stained for mast cells and eosinophils. These data were correlated to clinical and survival data from all patients.RESULTS:Fifty-three percent of cases were positive for IL-9 and 19% were positive for IL-9R in the cytoplasm of the tumour cells. The IL-9 positive patients had more eosinophils (P = 0.002) and mast cells (P = 0.02) in their tumours, more often a nodular sclerosis histology (P < 0.0001), a higher white-blood-cell count (P = 0.006) and a higher erythrocyte sedimentation rate (P = 0.003) at the time of diagnosis.CONCLUSIONS:IL-9 expression is related to the histology, clinical picture and the presence of eosinophils and mast cells in HL. These results indicate that IL-9 is an important part of the cytokine network and inflammatory infiltrate in HL.
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| 4. |
- Glimelius, Ingrid, et al.
(författare)
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The effect of Eosinophil cationic protein (ECP) on Hodgkin lymphoma cell lines
- 2011
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Ingår i: Experimental Hematology. - : Elsevier BV. - 0301-472X .- 1873-2399. ; 39:8, s. 850-858
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Tidskriftsartikel (refereegranskat)abstract
- Background In classical Hodgkin lymphoma (HL), many eosinophils in tumour tissue indicate poor prognosis, probably caused by stimulation of the tumour cells, the Hodgkin Reed Sternberg (HRS) cells. However, eosinophils are primarily known for their role in innate immunity, where one function is to secrete the toxic substances eosinophil cationic protein (ECP), and eosinophil protein X (EPX). The aim of this study was to investigate the effects of ECP on HRS cells in vitro.Method The fluorometric microculture cytotoxicity-assay (FMCA) measured survival index (SI) of cells from the HL cell lines HDLM-2, KMH2, and L428 after incubation with ECP or EPX. The gene products of a coding ECP polymorphism, ECP97arg and ECP97thr, and ECPs, with different levels of glycosylation were investigated. Flow cytometry was used to monitor the effects of ECP on markers of cell death.Results A concentration dependent reduction of SI was seen after ECP treatment. For the B-cell derived cell lines, KMH2 and L428, ECP was cytotoxic with a dose response relationship similar to a previously investigated small-cell lung cancer cell-line. In contrast, for HDLM-2, which is a cell line of T-cell origin, the cytotoxicity was even more pronounced at the lowest concentrations tested, and then reached a plateau at about 0.018µM. At a concentration of 0.14µM of ECP, an SI of 71%±1.9 was recorded for HDLM-2, which did not accentuate despite higher concentrations of ECP. ECP97arg and ECP97thr displayed similar cytotoxicity, and the level of glycosylation did not affect cytotoxicity for HDLM-2, in contrast to the small-cell lung cancer cell-line. For EPX, no or very limited reduction in SI was seen, compared to ECP (p<0.001). The majority of cells that died from ECP (the HDLM-2 cell line) were PI positive, and only a few were annexin V positive.Conclusions ECP is cytotoxic for HRS cells, but heterogeneity between cell lines was seen. The two cell lines of B-cell origin, KMH2 and L428, were sensitive to high ECP concentrations, but for HDLM-2, of T-cell origin, the cytotoxicity reached a plateau at higher concentrations. Thus, even at presumably high concentrations, ECP can be present around HRS cells without eradicating all cells.
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| 5. |
- Hedström, Gustaf, et al.
(författare)
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Mast cell infiltration is a favourable prognostic factor in diffuse large B-cell lymphoma
- 2007
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Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 138:1, s. 68-71
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Tidskriftsartikel (refereegranskat)abstract
- Previous studies indicate that the inflammatory response in diffuse large B-cell lymphomas (DLBCL) is important for the clinical outcome. Mast cells are key regulators in this response; we investigated whether the number of tryptase-positive mast cells is correlated with clinical outcome. Patients with many mast cells had a significantly better event-free survival (EFS) compared to those with few mast cells (P < 0.03 in both germinal centre (GC) and non-GC DLBCL. This supports the idea that the infiltration of mast cells is a reflection of the host inflammatory response and is related to a favourable outcome.
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| 6. |
- Englund, Annika
(författare)
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Hodgkin Lymphoma in children, adolescents and young adults
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Hodgkin lymphoma (HL) is a heterogeneous condition varying from engaging one single lymph node site to a widespread condition. The prognosis with contemporary treatment is excellent for the vast majority. However, the treatment might cause severe late adverse effects in a proportion of the affected individuals.We evaluated all children and adolescents diagnosed in Sweden and registered in the Swedish Childhood Cancer Register over a period of 25 years. The incidence has been stable and the overall survival (OS) is very good, comparable to the best results in the world. Approximately ten percent encountered a relapse, but even after relapse the chances of survival were good. During the study period there were no detectable changes in survival estimates. The use of radiotherapy has decreased.Epstein Barr virus (EBV) and numbers of eosinophils, mast cells and macrophages in the tumors were investigated in 98 cases. Young children were more likely to express EBV. In patients with advanced disease the mast cell and macrophage counts were higher and they also had more affected laboratory parameters. Patients with Nodular Lymphocyte Predominant Hodgkin Lymphoma did not express EBV in the tumor, had significantly lower numbers of eosinophils, mast cells and macrophages and less affected laboratory parameters compared to classical HL.Outcome and clinical presentation were investigated in a cohort of children, adolescents and young adults in Sweden and Denmark and treatment in pediatric and adult departments was compared. OS and event-free survival (EFS) did not differ between the three age groups nor between pediatric and adult treatment. However, the Danish pediatric patients had lower EFS, which corresponded to less use of radiotherapy. Adolescents and young adults shared similar characteristics, while children presented differently with less advanced disease and male preponderance.Hospitalization rates and outpatient visits after end of treatment were evaluated to see whether the excess need of resources described in the literature is evenly distributed among the survivors or whether it is limited to a smaller group. Most of the patients had a low burden of health care use and the relapsing patients were the main drivers of the excess need.
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| 7. |
- Englund, Annika, et al.
(författare)
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The role of tumour-infiltrating eosinophils, mast cells and macrophages in Classical and Nodular Lymphocyte Predominant Hodgkin Lymphoma in children
- 2016
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Ingår i: European Journal of Haematology. - : Wiley. - 0902-4441 .- 1600-0609. ; 97:5, s. 430-438
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: To study Hodgkin lymphoma (HL) microenvironment in a Swedish paediatric population and its relation to clinical parameters.METHODS: Tumour tissue from classical HL (cHL) (n=87) and nodular lymphocyte predominant HL (NLPHL) (n=11) was investigated for Epstein-Barr Virus (EBV) and analysed for eosinophils, mast cells and macrophages.RESULTS: In cHL, EBV positivity was more common in low age (p<0.001) and in mixed cellularity (MC) (p<0.001). Higher mast cell infiltration was seen in stage III-IV (p<0.001), and with presence of B-symptoms (p=0.01). Cases with high mast cell counts displayed higher erythrocyte sedimentation rate (ESR), lower haemoglobin and albumin levels. Higher macrophage infiltration was seen in stage III-IV (p=0.02) and there was elevated ESR and neutrophil count. All NLPHL cases were EBV negative, had lower rates of inflammatory cells and lower degree of inflammatory reaction in laboratory parameters. There was no difference in survival estimates with regard to infiltration of inflammatory cells.CONCLUSIONS: Higher levels of mast cells and macrophages in cHL tumours reflected the clinical presentation in laboratory parameters, B-symptoms and more advanced stages. NLPHL differs from cHL in numbers of inflammatory cells in the tumour, and in laboratory parameters. This article is protected by copyright. All rights reserved.
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| 8. |
- Gholiha, Alex Reza, et al.
(författare)
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Checkpoint CD47 expression in classical Hodgkin lymphoma
- 2022
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Ingår i: British Journal of Haematology. - : John Wiley & Sons. - 0007-1048 .- 1365-2141. ; 197:5, s. 580-589
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Tidskriftsartikel (refereegranskat)abstract
- The glycoprotein CD47 regulates antiphagocytic activity via signal regulatory protein alpha (SIRPa). This study investigated CD47 expression on Hodgkin and Reed–Sternberg (HRS) cells in the classical Hodgkin lymphoma (cHL) tumour microenvironment and its correlation with prognosis, programmed-death (PD) immune markers, and SIRPa+ leukocytes. We conducted immunohistochemistry with CD47 and SIRPa antibodies on diagnostic biopsies (tissue microarrays) from cHL patients from two cohorts (n = 178). In cohort I (n = 136) patients with high expression of CD47 on HRS cells (n = 48) had a significantly inferior event-free survival [hazard ratio (HR) = 5.57; 95% confidence interval (CI), 2.78–11.20; p < 0.001] and overall survival (OS) (HR = 8.54; 95% CI, 3.19–22.90; p < 0.001) compared with patients with low expression (n = 88). The survival results remained statistically significant in multivariable Cox regression adjusted for known prognostic factors. In cohort II (n = 42) high HRS cell CD47 expression also carried shorter event-free survival (EFS) (HR = 5.96; 95% CI, 1.20–29.59; p = 0.029) and OS (HR = 5.61; 95% CI, 0.58–54.15; p = 0.136), although it did not retain statistical significance in the multivariable analysis. Further, high CD47 expression did not correlate with SIRPa+ leukocytes or PD-1, PD-L1 and PD-L2 expression. This study provides a deeper understanding of the role of CD47 in cHL during an era of emerging CD47 therapies.
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| 9. |
- Gholiha, Alex R., et al.
(författare)
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High tumour plasma cell infiltration reflects an important microenvironmental component in classic Hodgkin lymphoma linked to presence of B-symptoms
- 2019
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Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 184:2, s. 192-201
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Tidskriftsartikel (refereegranskat)abstract
- Plasma cells are important prognostic actors in different malignancies. The tumour microenvironmental composition in classic Hodgkin lymphoma (cHL) is a major prognostic key element; however, clinicopathological studies regarding plasma cells in cHL are lacking. The aim of this study was to investigate CD138+ (also termed SDC1+) plasma cell and IgG4 producing (IgG4+) plasma cells infiltration in the microenvironment of cHL. Immunohistochemistry with anti-CD138 and IgG4 antibodies was performed on diagnostic tumour biopsies from 124 patients with cHL, on tissue micro array (TMA). In 120 cases, CD138+ plasma cell-infiltration was associated with the presence of B-symptoms (P = 0·028) and advanced stage, IIB-IVB (P = 0·009). In multivariate analysis, CD138+ plasma cells correlated with eosinophil infiltration (P = 0·013). The subgroup of IgG4+ plasma cells was analysed in 122 cases and only correlated to CD138+ plasma cells (P = 0·004). Patients with high proportion of tumour infiltrating CD138+ plasma cells (defined as ≥10%), had a more inferior event-free survival (P = 0·007) and overall survival (P = 0·004) than patients with a low proportion of infiltrating CD138+ plasma cells (<10%), although significance was not maintained in multivariate analysis. In summary, a high proportion of tumour-associated plasma cells in cHL reflect an important component in the microenvironment of cHL.
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| 10. |
- Gholiha, Alex R., et al.
(författare)
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Immune-Proteome Profiling in Classical Hodgkin Lymphoma Tumor Diagnostic Tissue
- 2022
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Ingår i: Cancers. - : MDPI. - 2072-6694. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- In classical Hodgkin Lymphoma (cHL), immunoediting via protein signaling is key to evading tumor surveillance. We aimed to identify immune-related proteins that distinguish diagnostic cHL tissues (=diagnostic tumor lysates, n = 27) from control tissues (reactive lymph node lysates, n = 30). Further, we correlated our findings with the proteome plasma profile between cHL patients (n = 26) and healthy controls (n = 27). We used the proximity extension assay (PEA) with the OlinkTM multiplex Immuno-Oncology panel, consisting of 92 proteins. Univariate, multivariate-adjusted analysis and Benjamini–Hochberg’s false discovery testing (=Padj) were performed to detect significant discrepancies. Proteins distinguishing cHL cases from controls were more numerous in plasma (30 proteins) than tissue (17 proteins), all Padj < 0.05. Eight of the identified proteins in cHL tissue (PD-L1, IL-6, CCL17, CCL3, IL-13, MMP12, TNFRS4, and LAG3) were elevated in both cHL tissues and cHL plasma compared with control samples. Six proteins distinguishing cHL tissues from controls tissues were significantly correlated to PD-L1 expression in cHL tissue (IL-6, MCP-2, CCL3, CCL4, GZMB, and IFN-gamma, all p ≤0.05). In conclusion, this study introduces a distinguishing proteomic profile in cHL tissue and potential immune-related markers of pathophysiological relevance
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