scholarly journals Progranulin mediates immune evasion of pancreatic ductal adenocarcinoma through regulation of MHCI expression

2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Phyllis F. Cheung ◽  
JiaJin Yang ◽  
Rui Fang ◽  
Arianna Borgers ◽  
Kirsten Krengel ◽  
...  
Keyword(s):  
Overall Survival ◽  
T Cell ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Mhc Class I ◽  
Immune Evasion ◽  
Ductal Adenocarcinoma ◽  
Poor Overall Survival ◽  
T Cell Infiltration ◽  
Cancer Initiation ◽  
Underlying Mechanisms

AbstractImmune evasion is indispensable for cancer initiation and progression, although its underlying mechanisms in pancreatic ductal adenocarcinoma (PDAC) are not fully known. Here, we characterize the function of tumor-derived PGRN in promoting immune evasion in primary PDAC. Tumor- but not macrophage-derived PGRN is associated with poor overall survival in PDAC. Multiplex immunohistochemistry shows low MHC class I (MHCI) expression and lack of CD8+ T cell infiltration in PGRN-high tumors. Inhibition of PGRN abrogates autophagy-dependent MHCI degradation and restores MHCI expression on PDAC cells. Antibody-based blockade of PGRN in a PDAC mouse model remarkably decelerates tumor initiation and progression. Notably, tumors expressing LCMV-gp33 as a model antigen are sensitized to gp33-TCR transgenic T cell-mediated cytotoxicity upon PGRN blockade. Overall, our study shows a crucial function of tumor-derived PGRN in regulating immunogenicity of primary PDAC.

scholarly journals Progranulin promotes immune evasion of pancreatic adenocarcinoma through regulation of MHCI expression

2021 ◽  
Author(s):  
Phyllis F Cheung ◽  
JiaJin Yang ◽  
Kirsten Krengel ◽  
Kristina Althoff ◽  
Chi Wai Yip ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Evasion ◽  
Ductal Adenocarcinoma ◽  
Antibody Treatment ◽  
Poor Overall Survival ◽  
Autonomous Function ◽  
Cancer Initiation ◽  
Specific Cytotoxicity ◽  
Underlying Mechanisms

ABSTRACTImmune evasion is indispensable for cancer initiation and progression, although its underlying mechanisms in pancreatic ductal adenocarcinoma (PDAC) remain elusive. Here, we unveiled a cancer cell-autonomous function of PGRN in driving immune evasion in primary PDAC. Tumor- but not macrophage-derived PGRN was associated with poor overall survival in PDAC. Multiplex immunohistochemistry revealed low MHC class I (MHCI) expression and lack of CD8+ T cells infiltration in PGRN-high tumors. Inhibition of PGRN abrogated autophagy-dependent MHCI degradation and restored MHCI expression on PDAC cells. Antibody-based blockade of PGRN in a genetic PDAC mouse model remarkably decelerated tumor initiation and progression. Notably, tumors expressing LCMV-gp33 as model antigen were sensitized towards cytotoxic gp33-TCR transgenic T cells upon anti-PGRN antibody treatment. Overall, our study uncovered an unprecedented role of tumor-derived PGRN in regulating immunogenicity of primary PDAC.STATEMENT OF SIGNIFICANCEImmune evasion is a key property of PDAC, rendering it refractory to immunotherapy. Here we demonstrate that tumor-derived PGRN promotes autophagy-dependent MHCI degradation, while anti-PGRN increases intratumoral CD8 infiltration and blocks tumor progression. With recent advances in T cell-mediated approaches, PGRN represents a pivotal target to enhance tumor antigen-specific cytotoxicity.

Clinical Characteristics and Overall Survival in Patients with Anaplastic Pancreatic Cancer

2014 ◽  
Vol 80 (2) ◽  
pp. 117-123 ◽  
Author(s):  
Clancy J. Clark ◽  
Janani S. Arun ◽  
Rondell P. Graham ◽  
Lizhi Zhang ◽  
Michael Farnell ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Overall Survival ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Tumor Stage ◽  
Ductal Adenocarcinoma ◽  
Rank Test ◽  
Poor Overall Survival ◽  
Perioperative Morbidity ◽  
Log Rank Test ◽  
Kaplan Meier

Anaplastic pancreatic cancer (APC) is a rare undifferentiated variant of pancreatic ductal adenocarcinoma with poor overall survival (OS). The aim of this study was to evaluate the clinical outcomes of APC compared with differentiated pancreatic ductal adenocarcinoma. We conducted a retrospective review of all patients treated at the Mayo Clinic with pathologically confirmed APC from 1987 to 2011. After matching with control subjects with pancreatic ductal adenocarcinoma, OS was evaluated using Kaplan-Meier estimates and log-rank test. Sixteen patients were identified with APC (56.3% male, median age 57 years). Ten patients underwent exploration of whom eight underwent pancreatectomy. Perioperative morbidity was 60 per cent with no mortality. The median OS was 12.8 months. However, patients with APC who underwent resection had longer OS compared with those who were not resected, 34.1 versus 3.3 months ( P = 0.001). After matching age, sex, tumor stage, and year of operation, the median OS was similar between patients with APC and those with ductal adenocarcinoma treated with pancreatic resection, 44.1 versus 39.9 months, ( P = 0.763). Overall survival for APC is poor; however, when resected, survival is similar to differentiated pancreatic ductal adenocarcinoma.

Analysis of associations of CXCR3 ligands with immune microenvironment and aggressiveness in murine and human pancreatic ductal adenocarcinoma.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 762-762
Author(s):  
Andrew Cannon ◽  
Christopher M Thompson ◽  
Pranita Atri ◽  
Rakesh Bhatia ◽  
Sushil Kumar ◽  
...  
Keyword(s):  
Overall Survival ◽  
T Cell ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Nk Cell ◽  
Cd8 T Cell ◽  
High Expression ◽  
Ductal Adenocarcinoma ◽  
Bioinformatics Analyses ◽  
Dismal Prognosis ◽  
M1 Macrophage

762 Background: The complex milieu of cytokines within pancreatic ductal adenocarcinoma (PDAC) promotes tumor progression and immune suppression thereby contributing to the dismal prognosis of patients with PDAC. However, the roles of many cytokines, including CXCR3 ligands, in PDAC have not been thoroughly investigated. Methods: Bioinformatics analyses of PDAC microarray and TCGA datasets were used to identify cytokines overexpressed in PDAC, their association with patient survival as well as the expression of cognate cytokine receptors. Comparative analysis of cytokine expression in KrasLSL-G12D-P53LSL-R172H-Pdx1-Cre (KPC) and KrasLSL-G12D-Pdx1-Cre (KC) murine PDAC models were used to validate these findings. Pathway and CIBERSORT analyses were employed to determine mechanistic basis of altered survival associated with cytokines of interest. Results: Of the 149 cytokines analyzed, CXCR3 ligands CXCL9 and CXCL10 were highly and consistently overexpressed in PDAC datasets. Concurrently, CXCL9, CXCL10 and PF4 were overexpressed in the aggressive KPC murine model compared to the indolent KC model. CXCR3 showed robust expression in PDAC in microarray, TCGA and IHC analyses. Interestingly, high expression of CXCR3 ligands was associated with shorter overall survival (p = 0.04 for CXCL9, 10 and 11 and p = 0.02 for PF4) while high expression of CXCR3 was associated with increased overall survival (p = 0.03). Pathway analysis of genes correlated with CXCR3 and/or its ligands showed that CXCR3 ligands may promote T-cell exhaustion (p < 0.001). Finally, CIBERSORT analysis of TCGA data demonstrated that high CXCR3 expression was associated with increased CD8 T-cell and naïve B-cell signatures and loss of plasma cells signatures. High CXCR3 ligand expression was associated with increased CD8 T-cell, and M1 macrophage, and loss of NK-cell signatures(p < 0.05). Conclusions: CXCR3 ligands are overexpressed in PDAC and are associated with poor survival, likely related to alterations in tumor immune infiltrate/activity and may represent targets to augment anti-tumor immunity.

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 Predicted CD4+ T cell infiltration levels could indicate better overall survival in sarcoma patients

2021 ◽  
Vol 49 (1) ◽  
pp. 030006052098153
Author(s):  
Qing Bi ◽  
Yang Liu ◽  
Tao Yuan ◽  
Huizhen Wang ◽  
Bin Li ◽  
...  
Keyword(s):  
Overall Survival ◽  
T Cell ◽  
Survival Data ◽  
Tumor Infiltrating Lymphocytes ◽  
The Cancer Genome Atlas ◽  
Cell Infiltration ◽  
T Cell Infiltration ◽  
Whole Exome ◽  
Cancer Genome Atlas ◽  
Infiltrating Lymphocytes

Objective The role of tumor-infiltrating lymphocytes (TILs) has not yet been characterized in sarcomas. The aim of this bioinformatics study was to explore the effect of TILs on sarcoma survival and genome alterations. Methods Whole-exome sequencing, transcriptome sequencing, and survival data of sarcoma were obtained from The Cancer Genome Atlas. Immune infiltration scores were calculated using the Tumor Immune Estimation Resource. Potential associations between abundance of infiltrating TILs and survival or genome alterations were examined. Results Levels of CD4+ T cell infiltration were associated with overall survival of patients with pan-sarcomas, and higher CD4+ T cell infiltration levels were associated with better survival. Somatic copy number alterations, rather than mutations, were found to correlate with CD4+ T cell infiltration levels. Conclusions This data mining study indicated that CD4+ T cell infiltration levels predicted from RNA sequencing could predict sarcoma prognosis, and higher levels of CD4+ T cells infiltration indicated a better chance of survival.

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