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.

Survival-Associated Alternative Messenger RNA Splicing Signatures in Pancreatic Ductal Adenocarcinoma: A Study Based on RNA-Sequencing Data

2019 ◽  
Vol 38 (11) ◽  
pp. 1207-1222
Author(s):  
Yu-Jie Zhou ◽  
Gui-Qi Zhu ◽  
Qing-Wei Zhang ◽  
Kenneth I. Zheng ◽  
Jin-Nan Chen ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Rna Sequencing ◽  
Rna Splicing ◽  
Messenger Rna ◽  
Ductal Adenocarcinoma ◽  
Sequencing Data

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 Synergy between Toxoplasma gondii type I ΔGRA17 immunotherapy and PD-L1 checkpoint inhibition triggers the regression of targeted and distal tumors

2021 ◽  
Vol 9 (11) ◽  
pp. e002970
Author(s):  
Yu-Chao Zhu ◽  
Hany M Elsheikha ◽  
Jian-Hua Wang ◽  
Shuai Fang ◽  
Jun-Jun He ◽  
...  
Keyword(s):  
Immune Response ◽  
Toxoplasma Gondii ◽  
Tumor Growth ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Immune Cell ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Complete Regression ◽  
Type I

BackgroundIn this study, we hypothesize that the ability of the protozoan Toxoplasma gondii to modulate immune response within the tumor might improve the therapeutic effect of immune checkpoint blockade. We examined the synergetic therapeutic activity of attenuated T. gondii RH ΔGRA17 strain and programmed death ligand-1 (PD-L1) treatment on both targeted and distal tumors in mice.MethodsThe effects of administration of T. gondii RH ΔGRA17 strain on the tumor volume and survival rate of mice bearing flank B16-F10, MC38, or LLC tumors were studied. We characterized the effects of ΔGRA17 on tumor biomarkers’ expression, PD-L1 expression, immune cells infiltrating the tumors, and expression of immune-related genes by using immunohistochemistry, immunofluorescence, flow cytometry, NanoString platform, and real-time quantitative PCR, respectively. The role of immune cells in the efficacy of ΔGRA17 plus PD-L1 blockade therapy was determined via depletion of immune cell subtypes.ResultsTreatment with T. gondii ΔGRA17 tachyzoites and anti-PD-L1 therapy significantly extended the survival of mice and suppressed tumor growth in preclinical mouse models of melanoma, Lewis lung carcinoma, and colon adenocarcinoma. Attenuation of the tumor growth was detected in the injected and distant tumors, which was associated with upregulation of innate and adaptive immune pathways. Complete regression of tumors was underpinned by late interferon-gamma-producing CD8+ cytotoxic T cells.ConclusionThe results from these models indicate that intratumoral injection of ΔGRA17 induced a systemic effect, improved mouse immune response, and sensitized immunologically ‘cold’ tumors and rendered them sensitive to immune checkpoint blockade therapy.

ERK Inhibition Improves Anti-PD-L1 Immune Checkpoint Blockade in Preclinical Pancreatic Ductal Adenocarcinoma

2021 ◽  
pp. molcanther.MCT-20-1112-A.2020
Author(s):  
Kelly E. Henry ◽  
Kyeara N. Mack ◽  
Veronica L. Nagle ◽  
Mike Cornejo ◽  
Adam O. Michel ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Ductal Adenocarcinoma ◽  
Erk Inhibition

scholarly journals Single-cell RNA transcriptome reveals the intra-tumoral heterogeneity and regulators underlying tumor progression in metastatic pancreatic ductal adenocarcinoma

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Qianhui Xu ◽  
Shaohuai Chen ◽  
Yuanbo Hu ◽  
Wen Huang
Keyword(s):  
Single Cell ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Rna Sequencing ◽  
Underlying Mechanism ◽  
Ductal Adenocarcinoma ◽  
Intratumor Heterogeneity ◽  
Sequencing Data ◽  
Multiple Tumor ◽  
Pathway Analyses ◽  
Differential Genes

AbstractPancreatic ductal adenocarcinoma (PDAC) is the most frequent and aggressive pancreatic tumor characterized by high metastatic risk and special tumor microenvironment. To comprehensively delineate the complex intra-tumoral heterogeneity and the underlying mechanism during metastatic lesions malignant progression, single-cell RNA sequencing (scRNA-seq) was employed. PCA and TSNE were used for dimensionality reduction analysis and cell clustering. Find All Markers function was used to calculate differential genes in each cluster, and Do Heatmap function was used to plot the distribution of differential genes in each cluster. GSVA was employed to assign pathway activity estimates to individual cells. Lineage trajectory progression was inferred by monocle. CNV status was inferred to compare the heterogeneity among patients and subtypes by infercnv. Ligand-receptor interactions were identified by CellPhoneDB, and regulons network of cells was analyzed by SCENIC. Through RNA-sequencing of 6236 individual cells from 5 liver metastatic PDAC lesions, 10 major cell clusters are identified by using unbiased clustering analysis of expression profiling and well-known cell markers. Cells with high CNV level were considered as malignant cells and pathway analyses were carried out to highlight intratumor heterogeneity in PDAC. Pseudotime trajectory analysis revealed that components of multiple tumor-related pathways and transcription factors (TFs) were differentially expressed along PDAC progression. The complex cellular communication suggested potential immunotherapeutic targets in PDAC. Regulon network identified multiple candidates for promising cell-specific transcriptional factors. Finally, metastatic-related genes expression levels and signaling pathways were validated in bulk RNA Sequencing data. This study contributed a comprehensive single-cell transcriptome atlas and contributed into novel insight of intratumor heterogeneity and molecular mechanism in metastatic PDAC.

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 Development of a Prognostic Signature Based on Single-Cell RNA Sequencing Data of Immune Cells in Intrahepatic Cholangiocarcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Miao Su ◽  
Kuang-Yuan Qiao ◽  
Xiao-Li Xie ◽  
Xin-Ying Zhu ◽  
Fu-Lai Gao ◽  
...  
Keyword(s):  
Single Cell ◽  
Rna Sequencing ◽  
Intrahepatic Cholangiocarcinoma ◽  
Immune Cells ◽  
Immune Cell ◽  
Functional Enrichment ◽  
Marker Genes ◽  
Tissue Cell ◽  
Sequencing Data ◽  
Single Cell Rna Sequencing

Analysis of single-cell RNA sequencing (scRNA-seq) data of immune cells from the tumor microenvironment (TME) may identify tumor progression biomarkers. This study was designed to investigate the prognostic value of differentially expressed genes (DEGs) in intrahepatic cholangiocarcinoma (ICC) using scRNA-seq. We downloaded the scRNA-seq data of 33,991 cell samples, including 17,090 ICC cell samples and 16,901 ICC adjacent tissue cell samples regarded as normal cells. scRNA-seq data were processed and classified into 20 clusters. The immune cell clusters were extracted and processed again in the same way, and each type of immune cells was divided into several subclusters. In total, 337 marker genes of macrophages and 427 marker genes of B cells were identified by comparing ICC subclusters with normal subclusters. Finally, 659 DEGs were obtained by merging B cell and macrophage marker genes. ICC sample clinical information and gene expression data were downloaded. A nine-prognosis-related-gene (PRG) signature was established by analyzing the correlation between DEGs and overall survival in ICC. The robustness and validity of the signature were verified. Functional enrichment analysis revealed that the nine PRGs were mainly involved in tumor immune mechanisms. In conclusion, we established a PRG signature based on scRNA-seq data from immune cells of patients with ICC. This PRG signature not only reflects the TME immune status but also provides new biomarkers for ICC prognosis.

The prognostic and predictive implications of the 12-chemokine score in muscle invasive bladder cancer.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 466-466
Author(s):  
Logan Zemp ◽  
Anders E. Berglund ◽  
Jasreman Dhillon ◽  
Ryan Putney ◽  
Youngchul Kim ◽  
...  
Keyword(s):  
Overall Survival ◽  
Bladder Cancer ◽  
Immune Checkpoint ◽  
Immune Cell ◽  
Progression Free Survival ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Sequencing Data ◽  
Lymphoid Aggregate ◽  
Type Iii

466 Background: Adaptive anti-tumor immunity can be orchestrated by lymph node-like immune cell aggregates within the tumor microenvironment (TME) called tertiary lymphoid structures (TLSs). TLSs are postulated to be the gateway of lymphocyte infiltration into the TME, and are privileged sites for coordinated tumor antigen presentation and lymphocyte priming, differentiation, and proliferation, leading to a robust tumor-specific immune response. A 12-chemokine metagene grouping (12-CK score) has previously been described that correlates with the presence of TLSs in other solid tumor types. In this study, we explored the prognostic implication of the 12-CK score in bladder cancer and its correlation with the presence of TLSs. Methods: Cystectomy specimens from 132 patients with bladder cancer were arrayed on Affymetrix microarrays. 12-CK scores were normalized with > 1 denoting high scores (12-CKHi). Immunohistochemistry (IHC) antibody staining was performed for DC-LAMP, CD20, CD4, and CD8. A GU pathologist scored TLSs into Types I-III, with type III representing fully developed TLSs. The Fisher’s exact test was used to test the associations between the 12-CK scores and the type of lymphoid aggregate. Overall survival was estimated using the Kaplan Meier method. Findings were validated using 12-CK scores extracted from TCGA transcriptome sequencing data and the IMvigor210CoreBiologies package. Results: Twenty-five (n = 25) patients had 12CK scores > 1 and were classified as 12CK-High. Pathologic review of 43 bladder tumor specimens confirmed higher levels of Type III TLS patients (33% vs. 9%, p = 0.03), B cells (p = 0.002), CD8 T cells (p = 0.01), and activated DC (p = 0.01) in 12-CKHi compared to 12-CKLo. 12-CKHi was found to have a progression-free survival (PFS, HR 0.29, p = 0.003, Fig1a), disease specific survival (DSS, HR 0.29, p = 0.004, Fig1b), and overall survival (OS, HR 0.55, p = 0.03, fig1c) advantage compared to 12-CKLo in the Moffitt patient cohort. These results were validated using the publically available RNA expression data from TCGA. TCGA patients with 12-CKHi (18%,n = 72) had improved PFS ( HR 0.55, p = 0.007, fig1d), DSS (HR = 0.40, p = 0.002, fig1e), and 0S (HR = 0.59, p = 0.01, fig1f). From the IMVIGOR-210 patient who were 12-CKHi were more likely to have a complete response (p < 0.05, fig1g) and have a 11.2mo OS benefit (fig1h) after treatment using atezolizumab. Conclusions: Three important findings emerged from the current study: 12CK-High scores corresponded with formation of TLS in the TME; favorable prognosis in surgically treated MIBC patients; and CR in atezolizumab-treated patients. The findings herein suggest the 12CK gene signature to be a clinically actable biomarker for predicting response to immune checkpoint blockade. We believe the 12CK signature may serve as an important tool to refine patient selection for immune checkpoint blockade treatment.

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