Stromal hyaluronan accumulation is associated with low immune response and poor prognosis in pancreatic cancer

AbstractHyaluronan (HA) accumulation has been associated with poor survival in various cancers, but the mechanisms for this phenomenon are still unclear. The aim of this study was to investigate the prognostic significance of stromal HA accumulation and its association with host immune response in pancreatic ductal adenocarcinoma (PDAC). The study material consisted of 101 radically treated patients for PDAC from a single geographical area. HA staining was evaluated using a HA-specific probe, and the patterns of CD3, CD8, CD73 and PD-L1 expression were evaluated using immunohistochemistry. HA staining intensity of tumour stromal areas was assessed digitally using QuPath. CD3- and CD8-based immune cell score (ICS) was determined. High-level stromal HA expression was significantly associated with poor disease-specific survival (p = 0.037) and overall survival (p = 0.013) In multivariate analysis, high-level stromal HA expression was an independent negative prognostic factor together with histopathological grade, TNM stage, CD73 positivity in tumour cells and low ICS. Moreover, high-level stromal HA expression was associated with low ICS (p = 0.017). In conclusion, stromal HA accumulation is associated with poor survival and low immune response in PDAC.

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CXCR4 inhibition in human pancreatic and colorectal cancers induces an integrated immune response

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2013644117 ◽

2020 ◽

Vol 117 (46) ◽

pp. 28960-28970 ◽

Cited By ~ 1

Author(s):

Daniele Biasci ◽

Martin Smoragiewicz ◽

Claire M. Connell ◽

Zhikai Wang ◽

Ya Gao ◽

...

Keyword(s):

Pancreatic Cancer ◽

Immune Response ◽

T Cell ◽

Chemokine Receptors ◽

Immune Cell ◽

Antibody Therapy ◽

Transcriptional Analysis ◽

Human Pancreatic Cancer ◽

Ductal Adenocarcinoma ◽

Colorectal Cancers

Inhibition of the chemokine receptor CXCR4 in combination with blockade of the PD-1/PD-L1 T cell checkpoint induces T cell infiltration and anticancer responses in murine and human pancreatic cancer. Here we elucidate the mechanism by which CXCR4 inhibition affects the tumor immune microenvironment. In human immune cell-based chemotaxis assays, we find that CXCL12-stimulated CXCR4 inhibits the directed migration mediated by CXCR1, CXCR3, CXCR5, CXCR6, and CCR2, respectively, chemokine receptors expressed by all of the immune cell types that participate in an integrated immune response. Inhibiting CXCR4 in an experimental cancer medicine study by 1-wk continuous infusion of the small-molecule inhibitor AMD3100 (plerixafor) induces an integrated immune response that is detected by transcriptional analysis of paired biopsies of metastases from patients with microsatellite stable colorectal and pancreatic cancer. This integrated immune response occurs in three other examples of immune-mediated damage to noninfected tissues: Rejecting renal allografts, melanomas clinically responding to anti-PD1 antibody therapy, and microsatellite instable colorectal cancers. Thus, signaling by CXCR4 causes immune suppression in human pancreatic ductal adenocarcinoma and colorectal cancer by impairing the function of the chemokine receptors that mediate the intratumoral accumulation of immune cells.

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Prognostic Significance and Immune Infiltration of Microenvironment‐related Signatures in Pancreatic Cancer

10.21203/rs.3.rs-60885/v1 ◽

2020 ◽

Author(s):

Qian Lu ◽

Yu Zhang ◽

Weihong Gu ◽

Xinrong Ji ◽

Zhong Chen

Keyword(s):

Pancreatic Cancer ◽

Overall Survival ◽

Immune Cell ◽

Differential Expression Analysis ◽

Prognostic Significance ◽

Ductal Adenocarcinoma ◽

Immune Infiltration ◽

Protein Protein Interaction ◽

Tumor Tissues ◽

Cox Analysis

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the highly fatal and most aggressive types of malignancies and accounts for the vast majority of Pancreatic Cancer (PC). Numerous studies have reported that the tumor microenvironment (TME) was significantly correlated with the oncogenesis, progress, and prognosis of various malignancies. Therefore, mining of TME-related genes is reasonably important to improve the overall survival (OS) of patients with PDAC. Methods: The Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data (ESTIMATE) algorithm was applied to identify differential expressed genes (DEGs). Functional and pathway enrichment analyses, protein–protein interaction (PPI) network construction and module analysis, overall survival analysis and tumor immune estimation resource (TIMER) database analysis were then performed on DEGs. Results: Data analysis indicated that higher immune scores were correlated with better overall survival (P = 0.033). Differential expression analysis obtained 90 intersection genes influencing both stromal and immune scores. Among these intersection genes, CA9, EBI3, SPOCK2, WDFY4, CD1D and CCL22 were significantly correlated with OS in PDAC patients. Moreover, multivariate Cox analysis revealed that CA9, SPOCK2 and CD1D were the most significant prognostic genes, and were closely correlated with immune infiltration in TCGA cohort. Further analysis indicated that CD1D were significantly related with immune cell biomarkers for PDAC patients. Conclusions: In summary, our findings provide a more comprehensive insight into TME and show a list of prognostic immune associated genes in PDAC. However, further studies on these genes need to be performed to gain additional understanding of the association between TME and prognosis in PDAC.

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The prognostic significance of exosomal marker (CD63) expression using immunohistochemistry (IHC) in patients with pancreatic ductal adenocarcinoma (PDAC).

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e15730 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e15730-e15730

Author(s):

Moh'd M. Khushman ◽

Arun Bhardwaj ◽

Girijesh K. Patel ◽

Javier Laurini ◽

Kelly Roveda ◽

...

Keyword(s):

Cancer Progression ◽

Prognostic Significance ◽

Stage Iv ◽

Progression Free Survival ◽

Staining Intensity ◽

Ductal Adenocarcinoma ◽

Positive Correlation ◽

The Mean ◽

Metastatic Sites ◽

Cd63 Expression

e15730 Background: Exosomes are important mediators of intercellular communication, and play pivotal roles in cancer progression, metastasis and chemoresistance. Exosomal membranes are enriched in endosomes-specific tetraspanins (CD63 and CD9). In patients with PDAC, positive correlation between CD9 expression and overall survival (OS) was reported. However, CD63 expression was conserved in all patients without reported prognostic significance. Here, we explored the prognostic significance of CD63 expression using IHC in patients with PDAC of mixed gender and racial background. Methods: Between 2012 and 2016, 49 patients with PDAC treated at Mitchell Cancer Institute had available tissue (pancreatic resected tissue/biopsy [N = 29] or metastatic site biopsy liver, omentum or bone (N = 20)) for CD63 staining using IHC. Two pathologists independently scored the expression of CD63. Staining intensity was graded from 1-3. Staining percentage was estimated in 10% increments. Mean Quick-score (Intensity X Percentage of staining) was calculated. Unpaired t test was used for statistical analysis. Results: Median age was 64 years (range 42-85). 53% are males. 67% white, 27% African Americans (AA) and 6% are other ethnicities. 41% had stage IV disease while 49% had stage I, II and III. Tumor involved the head (51%), body (20%) and tail (29%). The mean CD63 Q score is slightly higher in AA compared to white (157 vs 149, P = 0.76). The mean CD63 Q score is higher in the pancreatic tissues compared to metastatic sites tissues (185 Vs 102, P = 0.0002). In our cohort, patients with mean CD63 Q score > = 140 had longer median OS compared to patients with mean Q score of < 140 (19 months Vs 3 months, P = 0.0003) and progression free survival (PFS) (12 months vs 1 month, P = 0.0043). Conclusions: In our cohort of patients with PDAC, there was no racial difference in CD63 expression between white and AA. The expression of CD63 is higher in the pancreas compared to metastatic sites (liver, omentum and bone). There is positive correlation between CD63 expression and PFS and OS. To our knowledge, this is the first study to show prognostic significance of CD63 expression in patients with PDAC using IHC.

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Prognostic Implications of Intratumoral and Peritumoral Infiltrating Lymphocytes in Pancreatic Ductal Adenocarcinoma

Current Oncology ◽

10.3390/curroncol28060371 ◽

2021 ◽

Vol 28 (6) ◽

pp. 4367-4376

Author(s):

Jung-Soo Pyo ◽

Byoung Kwan Son ◽

Hyo Young Lee ◽

Il Hwan Oh ◽

Kwang Hyun Chung

Keyword(s):

T Lymphocytes ◽

Immune Cell ◽

Meta Analysis ◽

Disease Free Survival ◽

Ductal Adenocarcinoma ◽

Free Survival ◽

Prognostic Implications ◽

Infiltrating Lymphocytes ◽

Disease Free ◽

Immune Cell Score

This study aimed to elucidate the prognostic implications of intratumoral and peritumoral infiltrating T-lymphocytes in pancreatic ductal adenocarcinoma (PDAC) through a meta-analysis. A total of 18 eligible studies and 2453 PDAC patients were included in the present study. Intratumoral and peritumoral infiltrating lymphocytes were evaluated using various markers, such as CD3, CD4, CD8, FOXP3, and immune cell score. The correlations between these parameters and overall and disease-free survival were investigated and used in the meta-analysis. High intratumoral infiltration of CD3-, CD4-, and CD8-expressing lymphocytes was significantly correlated with better overall survival (hazard ratio (HR) 0.747, 95% confidence interval (CI) 0.620–0.900, HR 0.755, 95% CI 0.632–0.902, and HR 0.754, 95% CI 0.611–0.930, respectively). However, there was no significant correlation between PDAC prognosis and intratumoral FOXP3 or immune cell score (HR 1.358, 95% CI 1.115–1.655 and HR 0.776, 95% CI 0.566–1.065, respectively). Moreover, there was no significant correlation between the prognosis and peritumoral infiltrating T-lymphocytes. In evaluations of disease-free survival, only high intratumoral CD4 infiltration was correlated with a better prognosis (HR 0.525, 95% CI 0.341–0.810). Our results showed that high intratumoral infiltrating lymphocytes were significantly correlated with a better PDAC prognosis. However, among the tumor-infiltrating lymphocytes, CD3, CD4, and CD8 had prognostic implications, but not FOXP3 and immune cell score.

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Gasdermin C as a potential prognostic biomarker and its correlation with immune infiltration in pancreatic ductal adenocarcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e16256 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e16256-e16256

Author(s):

Xianghou Xia ◽

Yang Yu ◽

Hongjian Yang ◽

Dehong Zou ◽

Canming Wang ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Cancer Cells ◽

Prognostic Value ◽

Immune Cell ◽

Prognostic Significance ◽

High Expression ◽

Ductal Adenocarcinoma ◽

Immune Infiltration ◽

Kaplan Meier ◽

Kaplan Meier Plotter

e16256 Background: Although pyroptosis is critical for macrophages against pathogen infection, its role in cancer cells remains elusive. GSDMC is a pyroptosis executioner newly identified in cancer cells and have been shown to facilitate inflammatory tumor death. However, the expression of GSDMC in Pancreatic Ductal Adenocarcinoma (PDAC), its prognostic significance and possible impact on reshaping tumor immune microenviroment in PDAC is still unknown. Methods: We investigated the expression level of GSDMC using TNM plotter with TCGA and GTEx databases, the prognostic value of GSDMC in PDAC using Kaplan-Meier plotter with TCGA, GTEx and TCGA databases. The correlations between GSDMC and immune infiltration in PDAC were calculated using TIMER2.0 and TIDE with TCGA database. We further validated the prognostic value of GSDMC with immunohistochemistry(IHC) staining on a tissue microarray of 172 cases of PDAC patients receiving treatment in our institution. Correlations between expression of GSDMC and tumor infiltration lymphacytes(TILs) cells were also analyzed on tissue samples of those 172 PDAC patients. Results: TNM plotter analysis shows that the expression of GSDMC in PDAC tumor tissue is 10.49 folds higher than it is in pancreatic normal tissues (p = 8.86*e-56). Results from Kaplan-Meier plotter analysis shows high expression of GSDMC is significantly correlated with poorer overall survival(OS), HR = 1.8(1.19−2.71) logrank P = 0.004 and shorter relapse free survival (RFS), HR = 4.6(1.94−10.88), Logrank P = 0.00014 in PDAC. Analysis with TIMER2.0 and TIDE platform shows that expression of GSDMC is positively correlated with immunosuppressive cells, Cancer Associated Fiberblast (CAF) and Meyloid Derived Tumor Suprresso Cells(MDTSC). IHC staining analysis results is also consistent with aformentioned bioinformatic analysis, showing that high GSDMC expression correlated with shorter OS and reduced Tils infiltration. Conclusions: Our findings suggest that high expression of GSDMC is related to poor prognosis and compromised immune cell infiltration in PDAC. GSDMC holds promise for serving as a valuable prognostic marker and therapeutic target in PDAC.

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Prognostic Value of Osteopontin Splice Variant-c Expression in Breast Cancers: A Meta-Analysis

BioMed Research International ◽

10.1155/2016/7310694 ◽

2016 ◽

Vol 2016 ◽

pp. 1-8 ◽

Cited By ~ 5

Author(s):

Chengcheng Hao ◽

Zhiyan Wang ◽

Yanan Gu ◽

Wen G. Jiang ◽

Shan Cheng

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Fixed Effects ◽

Prognostic Value ◽

Meta Analysis ◽

Prognostic Significance ◽

Breast Cancers ◽

Breast Cancer Patients ◽

Poor Survival ◽

High Level

Objectives.Osteopontin (OPN) is overexpressed in breast cancers, while its clinical and prognostic significance remained unclear. This study aimed to assess the prognostic value of OPN, especially its splice variants, in breast cancers.Methods.Data were extracted from eligible studies concerning the OPN and OPN-c expression in breast cancer patients and were used to calculate the association between OPN/OPN-c and survival. Two reviewer teams independently screened the literatures according to the inclusion and exclusion criteria based on quality evaluation. Following the processes of data extraction, assessment, and transformation, meta-analysis was carried outviaRevMan 5.3 software.Results. A total of ten studies involving 1,567 patients were included. The results demonstrated that high level OPN indicated a poor outcome in the OS (HR = 2.22, 95% CI: 1.23–4.00, andP=0.008; random-effects model) with heterogeneity (I2=62%) of breast cancer patients. High level OPN-c appeared to be more significantly associated with poor survival (HR = 2.14, 95% CI: 1.51–3.04, andP<0.0001; fixed-effects model) with undetected heterogeneity (I2=0%).Conclusions.Our analyses indicated that both OPN and OPN-c could be considered as prognostic markers for breast cancers. The high level of OPN-c was suggested to be more reliably associated with poor survival in breast cancer patients.

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High-Level Expression and Prognostic Significance of Matrix Metalloprotease-19 and Matrix Metalloprotease-20 in Human Pancreatic Ductal Adenocarcinoma

Pancreas ◽

10.1097/mpa.0000000000000569 ◽

2016 ◽

Vol 45 (7) ◽

pp. 1067-1072 ◽

Cited By ~ 2

Author(s):

Lu-Lu Zhai ◽

Yang Wu ◽

Chong-Yang Cai ◽

Qiang Huang ◽

Zhi-Gang Tang

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Prognostic Significance ◽

Ductal Adenocarcinoma ◽

Matrix Metalloprotease ◽

High Level Expression ◽

High Level

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LAG-3-Expressing Tumor-Infiltrating T Cells Are Associated with Reduced Disease-Free Survival in Pancreatic Cancer

Cancers ◽

10.3390/cancers13061297 ◽

2021 ◽

Vol 13 (6) ◽

pp. 1297

Author(s):

Lena Seifert ◽

Ioana Plesca ◽

Luise Müller ◽

Ulrich Sommer ◽

Max Heiduk ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Immune Cell ◽

Prognostic Significance ◽

Disease Free Survival ◽

Ductal Adenocarcinoma ◽

Inhibitory Receptors ◽

Free Survival ◽

Disease Free

T cells are the predominant immune cell population in the pancreatic tumor microenvironment. High CD8+ and Th1-polarized CD4+ T cell infiltration is associated with prolonged survival in human pancreatic ductal adenocarcinoma (PDAC). However, the expression pattern of co-stimulatory and inhibitory receptors by PDAC-infiltrating T cells and their prognostic significance are not well defined. In this study, we employed multiplex immunofluorescence to investigate the intratumoral expression of the co-stimulatory receptor inducible T-cell co-stimulator (ICOS), the inhibitory receptors lymphocyte-activation gene 3 (LAG-3), programmed death 1 (PD-1), and V-domain immunoglobulin suppressor of T cell activation (VISTA) by tumor-infiltrating T cells (CD3) in a cohort of 69 patients with resected PDAC. T cells were enriched particularly within the stromal area and were highly heterogeneous across tumors. Further, T cells were associated with prolonged disease-free survival (DFS). However, LAG-3 expression by PDAC-infiltrating T cells was correlated with reduced DFS. Our study highlights the biological importance of LAG-3 expression by tumor-infiltrating T cells. LAG-3+ T cells may represent a novel prognostic marker and a particularly attractive target for immunotherapeutic strategies in PDAC.

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