Quantitative, qualitative and spatial analysis of lymphocyte infiltration in periampullary and pancreatic adenocarcinoma

Lundgren, Sebastian; Elebro, Jacob; Heby, Margareta; Nodin, Björn; Leandersson, Karin; Micke, Patrick; Jirström, Karin; Mezheyeuski, Artur

doi:10.1002/ijc.32945

Cited by 35 publications

(42 citation statements)

References 52 publications

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“…NKT cells were more abundant in APC mutated tumors, which may well be explained by the fact that APC mutations were exclusively found in I-type tumors in the current cohort (4). The significantly lower infiltration of CD68 + macrophages in CDKN2A mutated tumors is in line with findings for other types of immune cells (12,22), but may also merely be due to the fact that CDKN2A mutations are more common in PBtype tumors (4). Moreover, in the present study, mDC infiltration was found to be higher in SMAD4 wt tumors, which is in line with a previous study using a different method to assess both immune cell infiltration and mutational status (23).…”

Section: Discussionsupporting

confidence: 92%

“…The results demonstrate that high infiltration of several immune cell populations, especially NKT cells, was significantly associated with favorable clinicopathological factors, which is in line with previous findings regarding T and B lymphocytes (12).…”

Section: Discussionsupporting

confidence: 91%

“…The TMAs were stained with 4' ,6-diamidino-2-phenylindole (Spectral DAPI, Akoya Bioscience, San Francisco, CA, United States) in order to visualize cell nuclei. Lymphocyte infiltration was analyzed as previously described (12).…”

Section: Tissue Microarray Construction and Multiplex Immunofluorescementioning

confidence: 99%

“…We have previously shown that the composition and spatial interaction of various subsets of T and B lymphocytes in the tumor microenvironment of resected periampullary adenocarcinoma affects clinical outcome, not least depending on morphological type (12). In this study, we set forth to investigate the composition of the innate immune landscape in these tumors, using high resolution multiplex immunofluorescence.…”

Section: Introductionmentioning

confidence: 99%

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Topographical Distribution and Spatial Interactions of Innate and Semi-Innate Immune Cells in Pancreatic and Other Periampullary Adenocarcinoma

et al. 2020

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Background: The clinical management of pancreatic and other periampullary neoplasms remains challenging. In contrast to other cancer types, immunotherapies are largely ineffective, and the reason for the deprived immune response and the immune inhibiting cellular composition is only fragmentarily understood. The aim of this study was to comprehensively map the abundance, topographic distribution and spatial interaction of innate and innate-like immune cells in the tumor microenvironment of periampullary adenocarcinoma. Methods: Multiplexed immunofluorescent imaging was performed on tissue microarrays with tumors from a consecutive cohort of 175 patients with resected periampullary adenocarcinoma. To obtain a detailed spatial analysis of immune cell infiltration, two multiplex immune panels including antibodies against CD3, NKp46, CD56, CD68, CD163 and CD1a, CD208, CD123, CD15, CD68 and pancytokeratin were applied. Results: The infiltration of natural killer (NK) and NK-like T (NKT) cells was lower in malignant compared to benign tissue. NKT cells were more abundant in intestinal type compared to pancreatobiliary type tumors, and were associated with more favorable clinicopathological features and a prolonged survival. The interaction of NKp46 + NKT cells with macrophages was also associated with a prolonged survival. Conclusions: This study provides a comprehensive map of the innate immune landscape in periampullary adenocarcinoma. NK cells, and even more so NKT cells, are revealed to be central players in the local immune response in a clinically relevant context.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 91%

Section: Tissue Microarray Construction and Multiplex Immunofluorescementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Topographical Distribution and Spatial Interactions of Innate and Semi-Innate Immune Cells in Pancreatic and Other Periampullary Adenocarcinoma

et al. 2020

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“…These findings suggest that CLEC3B may play an important role in immune infiltration of SCC. The correlations between CLEC3B and immune markers of immune cells (selected by investigating some relevant papers [27][28][29][30][31]) were analyzed in the TIMER database to explore the relationship between CLEC3B and immune infiltrating cells of ADC and SCC (Table 6). In SCC, CLEC3B expression was positively correlated with majority of gene markers of different functional T cells (CD8+ T, Th1, Th2, etc.…”

Section: Clec3b Expression Is Associated With Immune Infiltration In mentioning

confidence: 99%

CLEC3B as a potential diagnostic and prognostic biomarker in lung cancer and association with the immune microenvironment

et al. 2020

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Background: Lung cancer is the leading cause of cancer-related mortality globally. Discovering effective biomarkers for early diagnosis and prognosis is important to reduce the mortality rate and ensure efficient therapy for lung cancer patients. C-type lectin domain family 3 member B (CLEC3B) has been reported in various cancers, but its correlation with lung cancer remains elusive. Methods:The GEO, TCGA and Oncomine databases were analyzed to examine the expression of CLEC3B in lung cancer. The CLEC3B mRNA levels in 15 patient tissue samples were detected by real-time PCR and the CLEC3B protein levels in 34 patient tissue samples were detected by immunohistochemistry. A Chi-square test was performed to analyze the correlation of CLEC3B expression and clinicopathological factors. The diagnostic value of CLEC3B was revealed by receiver operating characteristic (ROC) curves. Univariate and multivariate Cox proportional hazards regression models and Kaplan-Meier plots were used to evaluate the prognostic value of CLEC3B in lung cancer. The TIMER database was used to evaluate the correlation of CLEC3B and immune infiltration. Gene set enrichment analysis revealed tumor-associated biological processes related to CLEC3B.Results: CLEC3B is significantly downregulated in lung cancer patients compared with nontumor controls according to database analysis and patient tissue sample detection (p < 0.001). Specifically, CLEC3B is significantly downregulated in stage IA lung cancer patients (p < 0.001) and has a high diagnostic accuracy (area under the receiver operating characteristic curve > 0.9). Moreover, low expression of CLEC3B is related to poor progression-free survival (HR = 0.60, 95% CI 0.49-0.74, p = 8.3e−07) and overall survival (HR = 0.66, 95% CI 0.58-0.75, p = 2.1e−10), indicating it as a risk factor for lung cancer. Multivariate analysis value showed that low expression of CLEC3B may be an independent risk factor for disease-free survival in lung cancer patients (HR = 0.655, 95% CI 0.430-0.996, Cox p = 0.048). In addition, we also investigated the potential role of CLEC3B in tumor-immune interactions and found that CLEC3B might be associated with the immune infiltration and immune activation of lung cancer, especially in squamous cell carcinoma.© The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article' s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article'

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NOX4 regulates TGFβ‐induced proliferation and self‐renewal in glioblastoma stem cells

et al. 2022

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Glioblastoma (GBM) is the most aggressive and common glioma subtype, with a median survival of 15 months after diagnosis. Current treatments have limited therapeutic efficacy; thus, more effective approaches are needed. The glioblastoma tumoural mass is characterised by a small cellular subpopulation – glioblastoma stem cells (GSCs) – that has been held responsible for glioblastoma initiation, cell invasion, proliferation, relapse and resistance to chemo‐ and radiotherapy. Targeted therapies against GSCs are crucial, as is understanding the molecular mechanisms that govern the GSCs. Transforming growth factor β (TGFβ) signalling and reactive oxygen species (ROS) production are known to govern and regulate cancer stem cell biology. Among the differentially expressed genes regulated by TGFβ in a transcriptomic analysis of two different patient‐derived GSCs, we found NADPH oxidase 4 (NOX4) as one of the top upregulated genes. Interestingly, when patient tissues were analysed, NOX4 expression was found to be higher in GSCs versus differentiated cells. A functional analysis of the role of NOX4 downstream of TGFβ in several patient‐derived GSCs showed that TGFβ does indeed induce NOX4 expression and increases ROS production in a NOX4‐dependent manner. NOX4 downstream of TGFβ regulates GSC proliferation, and NOX4 expression is necessary for TGFβ‐induced expression of stem cell markers and of the transcription factor nuclear factor erythroid 2‐related factor 2 (NRF2), which in turn controls the cell’s antioxidant and metabolic responses. Interestingly, overexpression of NOX4 recapitulates the effects induced by TGFβ in GSCs: enhanced proliferation, stemness and NRF2 expression. In conclusion, this work functionally establishes NOX4 as a key mediator of GSC biology.

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Quantitative, qualitative and spatial analysis of lymphocyte infiltration in periampullary and pancreatic adenocarcinoma

Cited by 35 publications

References 52 publications

Topographical Distribution and Spatial Interactions of Innate and Semi-Innate Immune Cells in Pancreatic and Other Periampullary Adenocarcinoma

Topographical Distribution and Spatial Interactions of Innate and Semi-Innate Immune Cells in Pancreatic and Other Periampullary Adenocarcinoma

CLEC3B as a potential diagnostic and prognostic biomarker in lung cancer and association with the immune microenvironment

NOX4 regulates TGFβ‐induced proliferation and self‐renewal in glioblastoma stem cells

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