scholarly journals Nerve fibers in the Tumor Microenvironment are co-localized with Tertiary Lymphoid Structures

2020 ◽  
Author(s):  
Lara R. Heij ◽  
Xiuxiang Tan ◽  
Jakob N. Kather ◽  
Jan M. Niehues ◽  
Shivan Sivakumar ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Immune Cells ◽  
Immune Cell ◽  
Nerve Fibers ◽  
Ductal Adenocarcinoma ◽  
Fiber Density ◽  
Tertiary Lymphoid Structures ◽  
Lymphoid Structures ◽  
Nerve Fiber Density ◽  
Small Nerve

ABSTRACTBackgroundB cells and tertiary lymphoid structures (TLS) are reported to be important in the improvement of survival of cancer patients. These secondary lymphoid organs have been associated with the generation of an anti-tumor response. Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancer types and the stromal architecture shapes the intratumoral heterogeneity. The stroma of PDAC is a complex system in which crosstalk takes place between cancer-associated fibroblasts, immune cells, endothelial cells and the cancer cells. Besides immune cells and fibroblasts, there is some limited data about the influence of nerve fibers on cancer progression.Patients and methodsNerve Fiber Density (NFD) was analysed in our cohort of 188 patients with Pancreatic Ductal Adenocarcinoma who underwent pancreatic surgery. We used immunohistochemistry and multiplex imaging to phenotype the immune cell infiltrate. The cell detection classifier measured distance from immune cell to cancer gland and with a heat map we could count TLS. By using Machine learning we were able to define the spatial distribution and counting Tertiary Lymphoid Structures.ResultsHigh NFD is significantly associated with prolonged overall survival (HR 1.676 (95%CI 1.126,2.495) for low vs. high NFD, p-value 0.0109). The immune cells surrounding the nerve fibers were phenotyped in B cells, T cells and dendritic follicular cells, matching a TLS. Here we show that small nerve fibers are located at the TLS in Pancreatic Cancer and a high Nerve Fiber Density combined with more than 5 TLS is associated with a better survival (HR 0.388 (95%CI 0.218, 0.689).ConclusionThe co-localization of small nerve fibers with TLS is a new finding which has not been described before. However the precise roles of these TLS and nerve fibers remains unknown. These findings unravel future pathways and has the potential to reach new directions into already existing targeted therapy.

scholarly journals PD1+ T-cells correlate with Nerve Fiber Density as a prognostic biomarker in patients with resected perihilar cholangiocarcinoma.

2022 ◽  
Author(s):  
Xiuxiang Tan ◽  
Mika Rosin ◽  
Simone Appinger ◽  
Jan Bednarsch ◽  
Dong Liu ◽  
...  
Keyword(s):  
T Cells ◽  
Nerve Fiber ◽  
Immune Cell ◽  
Prognostic Biomarker ◽  
Region Of Interest ◽  
Nerve Fibers ◽  
Perihilar Cholangiocarcinoma ◽  
Fiber Density ◽  
Nerve Fiber Density ◽  
Small Nerve

Background & Aims: Perihilar cholangiocarcinoma (pCCA) is a hepatobiliary malignancy. Nerve fiber invasion (NFI) shows cancer invading the nerve and is considered an aggressive feature. Nerve fiber density (NFD) consists of small nerve fibers without cancer invasion and is divided into high NFD (high numbers of small nerve fibers) or low NFD (low numbers of small nerve fibers). We aim to explore differences in immune cell populations and survival. Approach & Results: We applied multiplex immunofluorescence (mIF) on 47 pCCA surgically resected patients and investigated immune cell composition in the tumor microenvironment (TME) of nerve fiber phenotypes (NFI, high and low NFD). Group comparison was performed and overall survival (OS) was assessed. The NFI Region of Interest (ROI) was measured with highest CD68+ macrophage levels among 3 ROIs (NFI compared to tumor free p= 0.016 and to tumor p=0.034) and PD1 expression on CD8 and were more abundant in the tumor rather than NFI ROI (p= 0.004 and p= 0.0029 respectively). NFD compared to NFI, demonstrated co-expression of CD8+PD1+ as well as CD68+PD1+ to be significantly higher in high NFD patients (p= 0.027 and p= 0.044, respectively). The high NFD OS was 92 months median OS (95% CI:41-142), for low NFD 20 months ((95% CI: 4-36) and for NFI 19 months (95% CI 7-33). High NFD OS was significantly better compared to low NFD (p= 0.046) and NFI (p= 0.032). Conclusions: PD1+ T-cells correlate with high NFD as a prognostic biomarker, the biological pathway behind this needs to be investigated.

scholarly journals The Crosstalk Between Malignant Cells and Tumor-Promoting Immune Cells Relevant to Immunotherapy in Pancreatic Ductal Adenocarcinoma

2022 ◽  
Vol 9 ◽  
Author(s):  
Xuefei Liu ◽  
Ziwei Luo ◽  
Xuechen Ren ◽  
Zhihang Chen ◽  
Xiaoqiong Bao ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Rna Sequencing ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Immune Cell ◽  
Immune Checkpoint Blockade ◽  
Ductal Adenocarcinoma ◽  
Malignant Cells ◽  
Sequencing Data ◽  
Immunosuppressive Microenvironment

Background: Pancreatic ductal adenocarcinoma (PDAC) is dominated by an immunosuppressive microenvironment, which makes immune checkpoint blockade (ICB) often non-responsive. Understanding the mechanisms by which PDAC forms an immunosuppressive microenvironment is important for the development of new effective immunotherapy strategies.Methods: This study comprehensively evaluated the cell-cell communications between malignant cells and immune cells by integrative analyses of single-cell RNA sequencing data and bulk RNA sequencing data of PDAC. A Malignant-Immune cell crosstalk (MIT) score was constructed to predict survival and therapy response in PDAC patients. Immunological characteristics, enriched pathways, and mutations were evaluated in high- and low MIT groups.Results: We found that PDAC had high level of immune cell infiltrations, mainly were tumor-promoting immune cells. Frequent communication between malignant cells and tumor-promoting immune cells were observed. 15 ligand-receptor pairs between malignant cells and tumor-promoting immune cells were identified. We selected genes highly expressed on malignant cells to construct a Malignant-Immune Crosstalk (MIT) score. MIT score was positively correlated with tumor-promoting immune infiltrations. PDAC patients with high MIT score usually had a worse response to immune checkpoint blockade (ICB) immunotherapy.Conclusion: The ligand-receptor pairs identified in this study may provide potential targets for the development of new immunotherapy strategy. MIT score was established to measure tumor-promoting immunocyte infiltration. It can serve as a prognostic indicator for long-term survival of PDAC, and a predictor to ICB immunotherapy response.

scholarly journals The Immune System of Mesothelioma Patients: A Window of Opportunity for Novel Immunotherapies

2021 ◽  
Author(s):  
Fabio Nicolini ◽  
Massimiliano Mazza
Keyword(s):  
Immune System ◽  
Immune Cells ◽  
Immune Cell ◽  
Current Knowledge ◽  
Cell Types ◽  
Screening Strategies ◽  
Tertiary Lymphoid Structures ◽  
Lymphoid Structures ◽  
Review Current

The interplay between the immune system and the pleural mesothelium is crucial both for the development of malignant pleural mesothelioma (MPM) and for the response of MPM patients to therapy. MPM is heavily infiltrated by several immune cell types which affect the progression of the disease. The presence of organized tertiary lymphoid structures (TLSs) witness the attempt to fight the disease in situ by adaptive immunity which is often suppressed by tumor expressed factors. In rare patients physiological, pharmacological or vaccine-induced immune response is efficient, rendering their plasma a valuable resource of anti-tumor immune cells and molecules. Of particular interest are human antibodies targeting antigens at the tumor cell surface. Here we review current knowledge regarding MPM immune infiltration, MPM immunotherapy and the harnessing of this response to identify novel biologics as biomarkers and therapeutics through innovative screening strategies.

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

2021 ◽  
Vol 12 ◽  
Author(s):  
Willem de Koning ◽  
Diba Latifi ◽  
Yunlei Li ◽  
Casper H. J. van Eijck ◽  
Andrew P. Stubbs ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Immune Cells ◽  
Immune Cell ◽  
Ductal Adenocarcinoma ◽  
Marker Genes ◽  
Cell Type ◽  
Tissue Samples ◽  
Immune Cell Type ◽  
Different Types ◽  
Pdac Tissue

The immune response affects tumor biological behavior and progression. The specific immune characteristics of pancreatic ductal adenocarcinoma (PDAC) can determine the metastatic abilities of cancerous cells and the survival of patients. Therefore, it is important to characterize the specific immune landscape in PDAC tissue samples, and the effect of various types of therapy on that immune composition. Previously, a set of marker genes was identified to assess the immune cell composition in different types of cancer tissue samples. However, gene expression and subtypes of immune cells may vary across different types of cancers. The aim of this study was to provide a method to identify immune cells specifically in PDAC tissue samples. The method is based on defining a specific set of marker genes expressed by various immune cells in PDAC samples. A total of 90 marker genes were selected and tested for immune cell type-specific definition in PDAC; including 43 previously used, and 47 newly selected marker genes. The immune cell-type specificity was checked mathematically by calculating the “pairwise similarity” for all candidate genes using the PDAC RNA-sequenced dataset available at The Cancer Genome Atlas. A set of 55 marker genes that identify 22 different immune cell types for PDAC was created. To validate the method and the set of marker genes, an independent mRNA expression dataset of 24 samples of PDAC patients who received various types of (neo)adjuvant treatments was used. The results showed that by applying our method we were able to identify PDAC specific marker genes to characterize immune cell infiltration in tissue samples. The method we described enabled identifying different subtypes of immune cells that were affected by various types of therapy in PDAC patients. In addition, our method can be easily adapted and applied to identify the specific immune landscape in various types of tissue samples.

scholarly journals Immune Cell Modulation of the Extracellular Matrix Contributes to the Pathogenesis of Pancreatic Cancer

Biomolecules ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 901
Author(s):  
Ramiz S. Ahmad ◽  
Timothy D. Eubank ◽  
Slawomir Lukomski ◽  
Brian A. Boone
Keyword(s):  
Pancreatic Cancer ◽  
Extracellular Matrix ◽  
Immune Cells ◽  
Immune Cell ◽  
Treatment Strategies ◽  
Stellate Cells ◽  
Pancreatic Stellate Cells ◽  
Ductal Adenocarcinoma ◽  
Cellular Mechanisms ◽  
Novel Treatment Strategies

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a five-year survival rate of only 9%. PDAC is characterized by a dense, fibrotic stroma composed of extracellular matrix (ECM) proteins. This desmoplastic stroma is a hallmark of PDAC, representing a significant physical barrier that is immunosuppressive and obstructs penetration of cytotoxic chemotherapy agents into the tumor microenvironment (TME). Additionally, dense ECM promotes hypoxia, making tumor cells refractive to radiation therapy and alters their metabolism, thereby supporting proliferation and survival. In this review, we outline the significant contribution of fibrosis to the pathogenesis of pancreatic cancer, with a focus on the cross talk between immune cells and pancreatic stellate cells that contribute to ECM deposition. We emphasize the cellular mechanisms by which neutrophils and macrophages, specifically, modulate the ECM in favor of PDAC-progression. Furthermore, we investigate how activated stellate cells and ECM influence immune cells and promote immunosuppression in PDAC. Finally, we summarize therapeutic strategies that target the stroma and hinder immune cell promotion of fibrogenesis, which have unfortunately led to mixed results. An enhanced understanding of the complex interactions between the pancreatic tumor ECM and immune cells may uncover novel treatment strategies that are desperately needed for this devastating disease.

scholarly journals Infiltrating immune cells and gene mutations in pancreatic ductal adenocarcinoma

2016 ◽  
Vol 103 (9) ◽  
pp. 1189-1199 ◽  
Author(s):  
W.-Q. Wang ◽  
L. Liu ◽  
H.-X. Xu ◽  
C.-T. Wu ◽  
J.-F. Xiang ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Immune Cells ◽  
Gene Mutations ◽  
Ductal Adenocarcinoma

scholarly journals Local versus circulating immune cell populations in pancreatic ductal adenocarcinoma patients

HPB ◽  
2018 ◽  
Vol 20 ◽  
pp. S24-S25
Author(s):  
M.H. Gerber ◽  
B.B. DiVita ◽  
D. Delitto ◽  
J.L. Cioffi ◽  
S.M. Wallet ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Immune Cell ◽  
Ductal Adenocarcinoma ◽  
Cell Populations

scholarly journals Unique Spatial Immune Profiling in Pancreatic Ductal Adenocarcinoma with Enrichment of Exhausted and Senescent T Cells and Diffused CD47-SIRPα Expression

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1825 ◽  
Author(s):  
Alexandros Papalampros ◽  
Michail Vailas ◽  
Konstantinos Ntostoglou ◽  
Maria Lopez Chiloeches ◽  
Stratigoula Sakellariou ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Immune Cell ◽  
Single Agent ◽  
Poor Response ◽  
Tumor Stroma ◽  
Ductal Adenocarcinoma ◽  
Dominant Type ◽  
Therapeutic Modalities ◽  
Senescent Phenotype ◽  
Gene And Protein Expression

Background: Pancreatic ductal adenocarcinoma (PDAC) is resistant to single-agent immunotherapies. To understand the mechanisms leading to the poor response to this treatment, a better understanding of the PDAC immune landscape is required. The present work aims to study the immune profile in PDAC in relationship to spatial heterogeneity of the tissue microenvironment (TME) in intact tissues. Methods: Serial section and multiplex in situ analysis were performed in 42 PDAC samples to assess gene and protein expression at single-cell resolution in the: (a) tumor center (TC), (b) invasive front (IF), (c) normal parenchyma adjacent to the tumor, and (d) tumor positive and negative draining lymph nodes (LNs). Results: We observed: (a) enrichment of T cell subpopulations with exhausted and senescent phenotype in the TC, IF and tumor positive LNs; (b) a dominant type 2 immune response in the TME, which is more pronounced in the TC; (c) an emerging role of CD47-SIRPα axis; and (d) a similar immune cell topography independently of the neoadjuvant chemotherapy. Conclusion: This study reveals the existence of dysfunctional T lymphocytes with specific spatial distribution, thus opening a new dimension both conceptually and mechanistically in tumor-stroma interaction in PDAC with potential impact on the efficacy of immune-regulatory therapeutic modalities.

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