High CXCR4 expression in pancreatic ductal adenocarcinoma as characterized by an inflammatory tumor phenotype with potential implications for an immunotherapeutic approach.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4021-4021
Author(s):  
Andreas Seeber ◽  
Florian Kocher ◽  
Andreas Pircher ◽  
Alberto Puccini ◽  
Yasmine Baca ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Immune Cell ◽  
Tumor Regression ◽  
Signal Transduction Pathway ◽  
Cxcr4 Expression ◽  
Ductal Adenocarcinoma ◽  
Rna Expression ◽  
Primary Tumors ◽  
Pathway Gene ◽  
Molecular Landscape

4021 Background: Immunotherapy is considered ineffective in the majority of patients with pancreatic ductal adenocarcinoma (PDAC), a consequence of a highly immunosuppressive tumor microenvironment (TME). However, treatment induced inhibition of CXC chemokine receptor 4 (CXCR4) and programmed cell death protein-1 (PD-1) in the COMBAT trial caused T cell infiltration and tumor regression in a subset of PDAC patients. Elucidating a phenotype that predicts response is clinically relevant. We performed a comprehensive molecular landscape study in PDAC evaluating CXCR4 RNA expression. Methods: 3,647 PDAC specimens were centrally analysed. NextGen DNA sequencing (NextSeq, 592 gene panel or NovaSeq, whole-exome sequencing), whole-transcriptome RNA sequencing (NovaSeq) and immunohistochemistry (Caris Life Sciences, Phoenix, AZ) were performed. Gene expression is reported as TPM (Transcripts per million). Pathway gene enrichment analyses were done using GSEA (Subramaniam 2015, PNAS). Immune cell fraction was calculated by QuantiSeq (Finotello 2019, Genome Medicine). The cohort was stratified in quartiles according to CXCR4 RNA expression status. Results: Overall, CXCR4 expression was higher in primary tumors compared to distant metastasis (38 vs. 28 TPM, p < 0.0001). CXCR4-high (top quartile: > 59 TPMs), when compared to CXCR4-low (bottom quartile: < 17 TPM) PDACs, were characterized by a high prevalence of mutations in signal transduction pathway genes (e.g. GNAS: 3.6 vs. 0.5%), an increased infiltration of immune cells (e.g. CD8+ T cells, M1 macrophages), and a higher expression of HLA-DRA and HLA-E (all p < 0.0001). We detected an upregulation of CXCL9, CXCL10, CXCL12, CCL5, IDO1 and LAG3 in CXCR4-high compared to CXCR4-low tumors. In contrast, lower PD-L1 expression (17.4 vs. 13.1%, p = 0.02), genomic loss of heterozygosity (17.4 vs. 10.8%), and a lower frequency of gene amplifications in ERBB2 (2.1 vs. 0.1%), TNFRSF14 (2.0 vs. 0.1%), and TP53 (82 vs. 73%, all p < 0.0001) were observed. Moreover, CXCR4-high expression was associated with a better survival (HR: 1.417, 95% CI [1.168-1.72], p < 0.001). Conclusions: This is the first study comprehensively investigating the molecular landscape of PDACs according to CXCR4 RNA expression. High CXCR4 expression is associated with an improved survival and a pro-inflammatory phenotype that may identify a subset of tumors with greater responsiveness to immunotherapeutic approaches.

scholarly journals A novel 20-gene prognostic score in pancreatic adenocarcinoma

2019 ◽  
Author(s):  
Secil Demirkol Canli ◽  
Ege Dedeoglu ◽  
Muhammad Waqas Akbar ◽  
Baris Kucukkaraduman ◽  
Murat Isbilen ◽  
...  
Keyword(s):  
Immune Cell ◽  
Prognostic Score ◽  
Performance Status ◽  
Cyclin B1 ◽  
Pancreatic Tissue ◽  
Tnm Staging ◽  
Prognostic Indicators ◽  
Ductal Adenocarcinoma ◽  
Primary Tumors ◽  
And Performance

Abstract Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal cancers. Known risk factors for this disease are currently insufficient in predicting mortality. The only FDA approved prognostic biomarker for PDAC patients is CA19-9. This, along with AJCC TNM staging and performance status, are considered important prognostic indicators in clinical practice. In order to better prognosticate patients with PDAC, we identified a novel panel of genes by utilizing publically available microarray and RNAseq data of PDAC tumors from GEO and TCGA. Expression of 20 genes were significantly associated with overall survival in four datasets and event-free survival in TCGA. A score generated based on the expression matrix of these genes could be validated in two independent cohorts. We find that this “Pancreatic cancer prognostic score 20 – PPS20” is dramatically elevated in metastatic tissue compared to primary tumor, and is higher in primary tumors compared to normal pancreatic tissue. Transcriptomic analyses show that tumors with low PPS20 have overall more immune cell infiltration and a higher CD8 T cell/Treg ratio when compared to those with high PPS20. Analyses of proteomic data from TCGA PAAD indicated higher levels of Cyclin B1, RAD51, EGFR and a lower E-cadherin/Fibronectin ratio in tumors with high PPS20. The PPS20 score defines not only prognostic and biological sub-groups but can predict response to targeted therapy options as well. Overall, PPS20 is a stronger and more robust transcriptomic signature when compared to similar, previously published gene lists.

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.

Combined SHP2 and ERK inhibition for the treatment of KRAS-driven Pancreatic Ductal Adenocarcinoma

2021 ◽  
Author(s):  
Katrin J Ciecielski ◽  
Antonio Mulero-Sanchez ◽  
Alexandra Berninger ◽  
Laura Ruiz Canas ◽  
Astrid Bosma ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Tumor Regression ◽  
Mapk Pathway ◽  
Single Agent ◽  
Ductal Adenocarcinoma ◽  
Good Tolerability ◽  
Recent Emergence ◽  
Erk Inhibition

Mutant KRAS is present in over 90% of pancreatic as well as 30-40% of lung and colorectal cancers and is one of the most common oncogenic drivers. Despite decades of research and the recent emergence of isoform-specific KRASG12C-inhibitors, most mutant KRAS isoforms, including the ones frequently associated with pancreatic ductal adenocarcinoma (PDAC), cannot be targeted directly. Moreover, targeting single RAS downstream effectors induces adaptive mechanisms leading to tumor recurrence or resistance. We report here on the combined inhibition of SHP2, a non-receptor tyrosine phosphatase upstream of KRAS, and ERK, a serine/threonine kinase and a key molecule downstream of KRAS in PDAC. This combination shows synergistic anticancer activity in vitro, superior disruption of the MAPK pathway, and significantly increased apoptosis induction compared to single-agent treatments. In vivo, we demonstrate good tolerability and efficacy of the combination. Concurrent inhibition of SHP2 and ERK induces significant tumor regression in multiple PDAC mouse models. Finally, we show evidence that 18F-FDG PET scans can be used to detect and predict early drug responses in animal models. Based on these compelling results, we will investigate this drug combination in a clinical trial (SHERPA, SHP2 and ERK inhibition in pancreatic cancer, NCT04916236), enrolling patients with KRAS-mutant PDAC.

Hyaluronan heterogeneity in pancreatic ductal adenocarcinoma: Primary tumors compared to sites of metastasis

Pancreatology ◽  
2021 ◽  
Author(s):  
Veronica R. Placencio-Hickok ◽  
Marie Lauzon ◽  
Natalie Moshayedi ◽  
Michelle Guan ◽  
Sungjin Kim ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Ductal Adenocarcinoma ◽  
Primary Tumors

scholarly journals Modulation of FoxO1 Expression by miR-21 to Promote Growth of Pancreatic Ductal Adenocarcinoma

2015 ◽  
Vol 35 (1) ◽  
pp. 184-190 ◽  
Author(s):  
Weifeng Song ◽  
Qi Li ◽  
Lei Wang ◽  
Liwei Wang
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Underlying Mechanism ◽  
Ductal Adenocarcinoma ◽  
Luciferase Reporter ◽  
Reporter Assay ◽  
Primary Tumors ◽  
Protein Levels ◽  
Infusion System

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal primary tumors in humans, with undetermined tumorigenesis. Although previous work by us, and by others, has clearly demonstrated an involvement of miR-21 in the growth of PDAC, the underlying mechanism has not been clarified. Methods: Here we analyzed the regulation of FoxO1 by miR-21 in vitro and in vivo, using luciferase-reporter assay and pancreatic intraductal infusion of antisense of miR-21, respectively. Results: We found that overexpression of miR-21 in PDAC cells decreased FoxO1 protein levels, whereas inhibition of miR-21 increased FoxO1 levels. Further, miR-21 bound to FoxO1 mRNA to prevent its translation through its 3'UTR. Moreover, administration of antisense of miR-21 through an intraductal infusion system significantly decreased miR-21 levels and increased FoxO1 levels in implanted PDAC, resulting in a significant decrease in PDAC growth. Conclusion: Taken together, our data highlight miR-21/FoxO1 axis as a novel therapeutic target for inhibiting the growth of PDAC.

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.

scholarly journals Tumor Size Matters—Understanding Concomitant Tumor Immunity in the Context of Hypofractionated Radiotherapy with Immunotherapy

Cancers ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 714
Author(s):  
Jean Philippe Nesseler ◽  
Mi-Heon Lee ◽  
Christine Nguyen ◽  
Anusha Kalbasi ◽  
James W. Sayre ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Immune Cell ◽  
Tumor Regression ◽  
Experimental Models ◽  
Tumor Burden ◽  
Local Regression ◽  
Cell Content ◽  
Primary Tumors ◽  
The Impact

The purpose of this study was to determine the dynamic contributions of different immune cell subsets to primary and abscopal tumor regression after hypofractionated radiation therapy (hRT) and the impact of anti-PD-1 therapy. A bilateral syngeneic FSA1 fibrosarcoma model was used in immunocompetent C3H mice, with delayed inoculation to mimic primary and microscopic disease. The effect of tumor burden on intratumoral and splenic immune cell content was delineated as a prelude to hRT on macroscopic T1 tumors with 3 fractions of 8 Gy while microscopic T2 tumors were left untreated. This was performed with and without systemic anti-PD-1. Immune profiles within T1 and T2 tumors and in spleen changed drastically with tumor burden in untreated mice with infiltrating CD4+ content declining, while the proportion of CD4+ Tregs rose. Myeloid cell representation escalated in larger tumors, resulting in major decreases in the lymphoid:myeloid ratios. In general, activation of Tregs and myeloid-derived suppressor cells allow immunogenic tumors to grow, although their relative contributions change with time. The evidence suggests that primary T1 tumors self-regulate their immune content depending on their size and this can influence the lymphoid compartment of T2 tumors, especially with respect to Tregs. Tumor burden is a major confounding factor in immune analysis that has to be taken into consideration in experimental models and in the clinic. hRT caused complete local regression of primary tumors, which was accompanied by heavy infiltration of CD8+ T cells activated to express IFN-γ and PD-1; while certain myeloid populations diminished. In spite of this active infiltrate, primary hRT failed to generate the systemic conditions required to cause abscopal regression of unirradiated microscopic tumors unless PD-1 blockade, which on its own was ineffective, was added to the RT regimen. The combination further increased local and systemically activated CD8+ T cells, but few other changes. This study emphasizes the subtle interplay between the immune system and tumors as they grow and how difficult it is for local RT, which can generate a local immune response that may help with primary tumor regression, to overcome the systemic barriers that are generated so as to effect immune regression of even small abscopal lesions.

scholarly journals Pancreatic cancer is marked by complement-high blood monocytes and tumor-associated macrophages

2021 ◽  
Vol 4 (6) ◽  
pp. e202000935
Author(s):  
Samantha B Kemp ◽  
Nina G Steele ◽  
Eileen S Carpenter ◽  
Katelyn L Donahue ◽  
Grace G Bushnell ◽  
...  
Keyword(s):  
Single Cell ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Rna Sequencing ◽  
Gene Expression Signature ◽  
Ductal Adenocarcinoma ◽  
Specific Gene ◽  
Sequencing Analysis ◽  
Tumor Associated Macrophages ◽  
Primary Tumors ◽  
Single Cell Rna Sequencing

Pancreatic ductal adenocarcinoma (PDA) is accompanied by reprogramming of the local microenvironment, but changes at distal sites are poorly understood. We implanted biomaterial scaffolds, which act as an artificial premetastatic niche, into immunocompetent tumor-bearing and control mice, and identified a unique tumor-specific gene expression signature that includes high expression of C1qa, C1qb, Trem2, and Chil3. Single-cell RNA sequencing mapped these genes to two distinct macrophage populations in the scaffolds, one marked by elevated C1qa, C1qb, and Trem2, the other with high Chil3, Ly6c2 and Plac8. In mice, expression of these genes in the corresponding populations was elevated in tumor-associated macrophages compared with macrophages in the normal pancreas. We then analyzed single-cell RNA sequencing from patient samples, and determined expression of C1QA, C1QB, and TREM2 is elevated in human macrophages in primary tumors and liver metastases. Single-cell sequencing analysis of patient blood revealed a substantial enrichment of the same gene signature in monocytes. Taken together, our study identifies two distinct tumor-associated macrophage and monocyte populations that reflects systemic immune changes in pancreatic ductal adenocarcinoma patients.

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