Identification, Validation, and Utilization of Immune Cells in Pancreatic Ductal Adenocarcinoma Based on Marker Genes

Koning, Willem de; Latifi, Diba; Li, Yunlei; Eijck, Casper H.J. van; Stubbs, Andrew; Mustafa, Dana A. M.

doi:10.3389/fimmu.2021.649061

Cited by 12 publications

(11 citation statements)

References 45 publications

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“…By using marker genes to define the cell types we assume that the immune cell’s genes are expressed in that specific cell type only (mutually exclusive) and that the expression of the marker genes is equal between cells for all samples. As a quality check of the cell definition based on previous research, pairwise similarities between the marker genes of each cell type were considered sufficient if R ≥ 0.6 ( Supplementary Figure S1 ) ( 28 ). Unfortunately, dendritic cell marker genes did not pass the quality control criteria, and therefore this cell type was not analyzed.…”

Section: Methodsmentioning

confidence: 99%

The Placental Innate Immune System Is Altered in Early-Onset Preeclampsia, but Not in Late-Onset Preeclampsia

et al. 2021

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Preeclampsia is a severe placenta-related pregnancy disorder that is generally divided into two subtypes named early-onset preeclampsia (onset <34 weeks of gestation), and late-onset preeclampsia (onset ≥34 weeks of gestation), with distinct pathophysiological origins. Both forms of preeclampsia have been associated with maternal systemic inflammation. However, alterations in the placental immune system have been less well characterized. Here, we studied immunological alterations in early- and late-onset preeclampsia placentas using a targeted expression profile approach. RNA was extracted from snap-frozen placenta samples (healthy n=13, early-onset preeclampsia n=13, and late-onset preeclampsia n=6). The expression of 730 immune-related genes from the Pan Cancer Immune Profiling Panel was measured, and the data were analyzed in the advanced analysis module of nSolver software (NanoString Technology). The results showed that early-onset preeclampsia placentas displayed reduced expression of complement, and toll-like receptor (TLR) associated genes, specifically TLR1 and TLR4. Mast cells and M2 macrophages were also decreased in early-onset preeclampsia compared to healthy placentas. The findings were confirmed by an immunohistochemistry approach using 20 healthy, 19 early-onset preeclampsia, and 10 late-onset preeclampsia placentas. We conclude that the placental innate immune system is altered in early-onset preeclampsia compared to uncomplicated pregnancies. The absence of these alterations in late-onset preeclampsia placentas indicates dissimilar immunological profiles. The study revealed distinct pathophysiological processes in early-onset and late-onset preeclampsia placentas and imply that a tailored treatment to each subtype is desirable.

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Section: Methodsmentioning

confidence: 99%

The Placental Innate Immune System Is Altered in Early-Onset Preeclampsia, but Not in Late-Onset Preeclampsia

et al. 2021

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“…To identify the immune cell types, candidate marker genes that define the cell types were tested for their specificity and stable expression, following our previously described method ( 34 ). The assumption for appropriate marker genes is that all selected genes for the same cell type decrease and increase in the same direction.…”

Section: Methodsmentioning

confidence: 99%

Spatial genomics reveals a high number and specific location of B cells in the pancreatic ductal adenocarcinoma microenvironment of long-term survivors

et al. 2023

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Background and aimOnly 10% of pancreatic ductal adenocarcinoma (PDAC) patients survive longer than five years. Factors underlining long-term survivorship in PDAC are not well understood. Therefore, we aimed to identify the key players in the tumor immune microenvironment (TIME) associated with long-term survivorship in PDAC patients.MethodsThe immune-related gene expression profiles of resected PDAC tumors of patients who survived and remained recurrence-free of disease for ≥36 months (long-term survivors, n=10) were compared to patients who had survived ≤6 months (short-term survivors, n=10) due to tumor recurrence. Validation was performed by the spatial protein expression profile of immune cells using the GeoMx™ Digital Spatial Profiler. An independent cohort of samples consisting of 12 long-term survivors and 10 short-term survivors, was used for additional validation. The independent validation was performed by combining qualitative immunohistochemistry and quantitative protein expression profiling.ResultsB cells were found to be significantly increased in the TIME of long-term survivors by gene expression profiling (p=0.018). The high tumor infiltration of B cells was confirmed by spatial protein profiling in the discovery and the validation cohorts (p=0.002 and p=0.01, respectively). The higher number of infiltrated B cells was found mainly in the stromal compartments of PDAC samples and was exclusively found within tumor cells in long-term survivors.ConclusionThis is the first comprehensive study that connects the immune landscape of gene expression profiles and protein spatial infiltration with the survivorship of PDAC patients. We found a higher number and a specific location of B cells in TIME of long-term survivors which emphasizes the importance of B cells and B cell-based therapy for future personalized immunotherapy in PDAC patients.

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“…( 13 ). The immune cell definition method using marker genes was improved to increase the specificity by “personalizing” the gene markers used to identify immune cell types for each type of tissue (e.g., cervical cancer) ( 14 ). In brief, the gene markers for each immune cell type were selected based on literature, then the correlation of genes that mark one cell type was calculated.…”

Section: Methodsmentioning

confidence: 99%

“…Data of all gene expression (not only the differentially expressed genes) were used to estimate the relative infiltration of immune cells following the method developed within the nSolver Advanced Analysis module by Danaher et al (13). The immune cell definition method using marker genes was improved to increase the specificity by "personalizing" the gene markers used to identify immune cell types for each type of tissue (e.g., cervical cancer) (14). In brief, the gene markers for each immune cell type were selected based on literature, then the correlation of genes that mark one cell type was calculated.…”

Section: Cell Type Calculationmentioning

confidence: 99%

Identifying Molecular Changes in Early Cervical Cancer Samples of Patients That Developed Metastasis

et al. 2022

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Cervical cancer is one of the most common cancers in women worldwide. Patients diagnosed with early-stage cervical cancer have a good prognosis, however, 10-20% suffer from local or distant recurrent disease after primary treatment. Treatment options for recurrent cervical cancer are limited. Therefore, it is crucial to identify factors that can predict patients with an increased risk of recurrence to optimize treatment to prevent the recurrence of cervical cancer. We aimed to identify biomarkers in early-stage primary cervical cancer which recurred after surgery. Formalin-Fixed, Paraffin-Embedded surgical specimens of 34 patients with early-stage cervical cancer (FIGO 2009 stage 1B1) and 7 healthy controls were analyzed. Targeted gene expression profiling using the PanCancer IO 360 panel of NanoString Technology was performed. The findings were confirmed by performing immunohistochemistry stainings. Various genes, namely GLS, CD36, WNT5a, HRAS, DDB2, PIK3R2, and CDH2 were found to be differentially highly expressed in primary cervical cancer samples of patients who developed distant recurrence. In addition, The relative infiltration score of CD8+ T cells, CD80+CD86+ macrophages, CD163+MRC1+ macrophages, and FOXP3+IL2RA+ regulatory T cells were significantly higher in this group of samples. In contrast, no significant differences in gene expression and relative immune infiltration were found in samples of patients who developed local recurrence. The infiltration of CD8 and FOXP3 cells were validated by immunohistochemistry using all samples included in the study. We identified molecular alterations in primary cervical cancer samples from patients who developed recurrent disease. These findings can be utilized towards developing a molecular signature for the early detection of patients with a high risk to develop metastasis.

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Identification, Validation, and Utilization of Immune Cells in Pancreatic Ductal Adenocarcinoma Based on Marker Genes

Cited by 12 publications

References 45 publications

The Placental Innate Immune System Is Altered in Early-Onset Preeclampsia, but Not in Late-Onset Preeclampsia

The Placental Innate Immune System Is Altered in Early-Onset Preeclampsia, but Not in Late-Onset Preeclampsia

Spatial genomics reveals a high number and specific location of B cells in the pancreatic ductal adenocarcinoma microenvironment of long-term survivors

Identifying Molecular Changes in Early Cervical Cancer Samples of Patients That Developed Metastasis

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