scholarly journals Gamma-delta T cells stimulate IL-6 production by pancreatic stellate cells in pancreatic ductal adenocarcinoma

2020 ◽  
Vol 146 (12) ◽  
pp. 3233-3240
Author(s):  
Adrian M. Seifert ◽  
Julian List ◽  
Max Heiduk ◽  
Rahel Decker ◽  
Janusz von Renesse ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
T Cells ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Pancreatic Tumor ◽  
Tumor Tissue ◽  
Stellate Cell ◽  
Γδ T Cells ◽  
Tumor Stroma ◽  
Pancreatic Stellate Cells ◽  
Ductal Adenocarcinoma

Abstract Introduction The immunosuppressive tumor microenvironment promotes progression of pancreatic ductal adenocarcinoma (PDAC). γδ T cells infiltrate the pancreatic tumor stroma and support tumorigenesis through αβ T cell inhibition. Pancreatic stellate cell (PSC) activation contributes to pancreatic fibrosis in PDAC, limiting the delivery and efficacy of therapeutic agents. Whether γδ T cells have direct effects on PSC activation is unknown. Methods In this study, we analyzed tumor tissue from 68 patients with PDAC and determined the frequency and location of γδ T cells using immunohistochemistry and immunofluorescence. PDAC samples from the TCGA database with low and high TRGC2 expression were correlated with the expression of extracellular matrix genes. Further, PSCs were isolated from pancreatic tumor tissue and co-cultured with γδ T cells for 48 hours and cytokine production was measured using a cytometric bead array. Results γδ T cells infiltrated the pancreatic tumor stroma and were located in proximity to PSCs. A high infiltration of γδ T cells was associated with increased expression of several extracellular matrix genes in human PDAC. In vitro, γδ T cells stimulated IL-6 production by PDAC-derived PSCs. Conclusion γδ T cells activated PSCs and modulation of this interaction may enhance the efficacy of combinational therapies in human PDAC.

scholarly journals 659 T cell receptor exchange by zygote engineering results in physiological T cell responses for therapeutic use in pancreatic ductal adenocarcinoma

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A687-A687
Author(s):  
Meagan Rollins ◽  
Jackson Raynor ◽  
Ebony Miller ◽  
Ellen Spartz ◽  
Walker Lahr ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Animal Studies ◽  
Tumor Stroma ◽  
Cell Receptor ◽  
Ductal Adenocarcinoma ◽  
University Of Minnesota ◽  
T Cell Therapy ◽  
High Affinity

BackgroundPancreatic ductal adenocarcinoma (PDA) is a lethal malignancy characterized by a highly suppressive tumor microenvironment. Despite this, engineered T cell therapy has promise for effectively targeting PDA. To identify the underlying mechanisms of antigen-specific engineered T cell immunosuppression in PDA, we create novel TCR knock-in mouse models for a robust and standardized source of naïve mesothelin (Msln)-specific T cells.MethodsSpecifically, we integrate two murine mesothelin-specific TCRs into the physiologic Trac locus in primary murine T cells and zygotes using CRISPR/Cas9 and rAAV expressing the TCR DNA. Simultaneously using CRISPR/Cas9, Msln was disrupted to circumvent T cell tolerance.ResultsThis strategy resulted in the rapid generation of homozygous TCR Trac knock-in mice and with homozygous null mutations in Msln. In these TCR-exchanged (TRex) mice, most T cells expressed the 1045 (high affinity) or 7431 (low affinity) as determined by tetramer staining. TRex T cells exhibit a naïve phenotype and rapidly differentiate into effector T cells upon antigenic stimulation. While the high affinity 1045 TCR elicits function in CD4 T cells, the lower affinity 7431 T cells exhibit a higher functional avidity and less TCR downregulation when antigen is limiting. Historical TCR transgenic T cells, in which the TCR is randomly integrated into the genome, exhibit increased PD1, CD25, and CD69, decreased functionality, and a bias to CD25-Foxp3+ Treg as compared to T cells from TRex mice. Further, TCR Trac integration in primary T cells retain superior function following repetitive antigenic stimulations retrovirally transduced T cells. Adoptive transfer of 1045 TRex T cells significantly prolongs survival of mice bearing autochthonous PDA. When combined with a vaccine, 1045 TRex T cells cause involution of the fibroinflammatory tumor stroma.ConclusionsIn sum, we rapidly generate mice that physiologically express the desired TCR, circumventing the shortcomings of standard T cell engineering strategies and TCR transgenic models.Ethics ApprovalUniversity of Minnesota Institutional Animal Care and Use Committee approved all animal studies to Dr. Ingunn Stromnes (2005-38115A.) Generation of TCR knockin (KI) animals was performed in the Mouse Genetic Laboratory at the University of Minnesota.

Influence of IP-10/CXCL10 induction in human pancreatic cancer stroma on lymphocytes recruitment and correlation with survival.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 290-290 ◽  
Author(s):  
Thomas B Brunner ◽  
Serena Lunardi ◽  
Nigel B Jamieson ◽  
Su Yin Lim ◽  
Kristin L Griffiths ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
T Cells ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Cancer Patients ◽  
Mononuclear Cells ◽  
Pancreatic Stellate Cells ◽  
Human Pancreatic Cancer ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Tumors ◽  
Pancreatic Cancer Cells

290 Background: Pancreatic ductal adenocarcinoma is characterized by an abundant desmoplastic reaction driven by pancreatic stellate cells (PSCs) that contributes to tumor progression. Here we sought to characterize the interactions between pancreatic cancer cells (PCCs) and PSCs that affect the inflammatory and immune response in pancreatic tumors. Methods: Conditioned media from mono- and cocultures of PSCs and PCCs were assayed for expression of cytokines, chemokines and growth factors. Gene expression analysis of human pancreatic ductal adenocarcinoma samples was used to verify expression of cytokines and their correlation with markers of immunoresponse and with clinical outcome. Finally, we tested chemotaxis of leukocytes isolated from peripheral blood mononuclear cells of pancreatic cancer patients. Results: IP-10/CXCL10 was the most highly induced chemokine in coculture of PSCs and PCCs. Its expression was induced in the PSCs by PCCs. IP-10 expression was consistently upregulated in human pancreatic cancer specimens, and positively correlated with high stroma content. Furthermore, expression of IP-10 and its receptor CXCR3 were significantly associated with the intratumoral presence of regulatory T cells (Tregs). In an independent cohort of 48 patients with resectable pancreatic ductal adenocarcinoma, the survival of patients with high IP-10 levels was 18.1 months less than those with low IP-10 levels (HR=2.14, 95% CI 1.05 -4.42). Importantly, IP-10 stimulated the ex vivo recruitment of CXCR3+ effector T cells as well as CXCR3+ Tregs derived from patients with pancreatic cancer. Conclusions: Our findings suggest that, in pancreatic cancer patients, CXCR3+ Tregs are recruited by IP-10 expressed by PSCs in the tumor stroma, leading to immunosuppressive and tumor-promoting effects.

scholarly journals The reciprocal regulation between host tissue and immune cells in pancreatic ductal adenocarcinoma: new insights and therapeutic implications

2019 ◽  
Vol 18 (1) ◽  
Author(s):  
Xiaomeng Liu ◽  
Jin Xu ◽  
Bo Zhang ◽  
Jiang Liu ◽  
Chen Liang ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Immune Cells ◽  
Immune Modulation ◽  
Tumor Tissue ◽  
Tumor Stroma ◽  
Immune Checkpoint Blockade ◽  
Ductal Adenocarcinoma ◽  
Reciprocal Regulation ◽  
Therapeutic Implications ◽  
Stromal Microenvironment

AbstractPancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death and is one of the most difficult-to-treat cancers. Surgical resection and adjuvant therapy have limited effects on the overall survival of PDAC patients. PDAC exhibits an immunosuppressive microenvironment, the immune response predicts survival, and activation of immune system has the potential to produce an efficacious PDAC therapy. However, chimeric antigen receptor T (CAR-T) cell immunotherapy and immune checkpoint blockade (ICB), which have produced unprecedented clinical benefits in a variety of different cancers, produce promising results in only some highly selected patients with PDAC. This lack of efficacy may be because existing immunotherapies mainly target the interactions between cancer cells and immune cells. However, PDAC is characterized by an abundant tumor stroma that includes a heterogeneous mixture of immune cells, fibroblasts, endothelial cells, neurons and some molecular events. Immune cells engage in extensive and dynamic crosstalk with stromal components in the tumor tissue in addition to tumor cells, which subsequently impacts tumor suppression or promotion to a large extent. Therefore, exploration of the interactions between the stroma and immune cells may offer new therapeutic opportunities for PDAC. In this review, we discuss how infiltrating immune cells influence PDAC development and explore the contributions of complex components to the immune landscape of tumor tissue. The roles of stromal constituents in immune modulation are emphasized. We also predict potential therapeutic strategies to target signals in the immune network in the abundant stromal microenvironment of PDAC.

scholarly journals Syndecans and Pancreatic Ductal Adenocarcinoma

Biomolecules ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 349
Author(s):  
Nausika Betriu ◽  
Juan Bertran-Mas ◽  
Anna Andreeva ◽  
Carlos E. Semino
Keyword(s):  
Extracellular Matrix ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Cell Types ◽  
Ductal Adenocarcinoma ◽  
Physiological Processes ◽  
Extracellular Matrix Components ◽  
Detection And Diagnosis ◽  
And Migration ◽  
Early Detection And Diagnosis

Pancreatic Ductal Adenocarcinoma (PDAC) is a fatal disease with poor prognosis because patients rarely express symptoms in initial stages, which prevents early detection and diagnosis. Syndecans, a subfamily of proteoglycans, are involved in many physiological processes including cell proliferation, adhesion, and migration. Syndecans are physiologically found in many cell types and their interactions with other macromolecules enhance many pathways. In particular, extracellular matrix components, growth factors, and integrins collect the majority of syndecans associations acting as biochemical, physical, and mechanical transducers. Syndecans are transmembrane glycoproteins, but occasionally their extracellular domain can be released from the cell surface by the action of matrix metalloproteinases, converting them into soluble molecules that are capable of binding distant molecules such as extracellular matrix (ECM) components, growth factor receptors, and integrins from other cells. In this review, we explore the role of syndecans in tumorigenesis as well as their potential as therapeutic targets. Finally, this work reviews the contribution of syndecan-1 and syndecan-2 in PDAC progression and illustrates its potential to be targeted in future treatments for this devastating disease.

scholarly journals Tumor-derived exosomal long noncoding RNA LINC01133, regulated by Periostin, contributes to pancreatic ductal adenocarcinoma epithelial-mesenchymal transition through the Wnt/β-catenin pathway by silencing AXIN2

Oncogene ◽  
2021 ◽  
Vol 40 (17) ◽  
pp. 3164-3179
Author(s):  
Yang Liu ◽  
Tianchi Tang ◽  
Xiaosheng Yang ◽  
Peng Qin ◽  
Pusen Wang ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Noncoding Rna ◽  
Pancreatic Tumor ◽  
Epithelial Mesenchymal Transition ◽  
Noncoding Rnas ◽  
Ductal Adenocarcinoma ◽  
Overall Survival Rate ◽  
Poor Overall Survival ◽  
Mesenchymal Transition ◽  
Pancreatic Cancer Cells

AbstractPancreatic ductal adenocarcinoma (PDAC) is one of the most fatal malignancies and rapidly progressive diseases. Exosomes and long noncoding RNAs (lncRNAs) are emerging as vital mediators in tumor cells and their microenvironment. However, the detailed roles and mechanisms of exosomal lncRNAs in PDAC progression remain unknown. Here, we aimed to clarify the clinical significance and mechanisms of exosomal lncRNA 01133 (LINC01133) in PDAC. We analyzed the expression of LINC01133 in PDAC and found that exosomal LINC01133 expression was high and positively correlated with higher TNM stage and poor overall survival rate of PDAC patients. Further research demonstrated that Periostin could increase exosome secretion and then enhance LINC01133 expression. In addition, Periostin increased p-EGFR, p-Erk, and c-myc expression, and c-myc could bind to the LINC01133 promoter region. These findings suggested that LINC01133 can be regulated by Periostin via EGFR pathway activity. We also observed that LINC01133 promoted the proliferation, migration, invasion, and epithelial–mesenchymal transition (EMT) of pancreatic cancer cells. We subsequently evaluated the effect of LINC01133 on the Wnt/β-catenin pathway and confirmed that LINC01133 can interact with Enhancer Of Zeste Homolog 2 (EZH2) and then promote H3K27 trimethylation. This can further silence AXIN2 and suppress GSK3 activity, ultimately activating β-catenin. Collectively, these data indicate that exosomal LINC01133 plays an important role in pancreatic tumor progression, and targeting LINC01133 may provide a potential treatment strategy for PDAC.

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.

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