Dataset Information

Galectins Are Central Mediators of Immune Escape in Pancreatic Ductal Adenocarcinoma.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers and is highly immune tolerant. Although there is immune cell infiltration in PDAC tissues, most of the immune cells do not function properly and, therefore, the prognosis of PDAC is very poor. Galectins are carbohydrate-binding proteins that are intimately involved in the proliferation and metastasis of tumor cells and, in particular, play a crucial role in the immune evasion of tumor cells. Galectins induce abnormal functions and reduce numbers of tumor-associated macrophages (TAM), natural killer cells (NK), T cells and B cells. It further promotes fibrosis of tissues surrounding PDAC, enhances local cellular metabolism, and ultimately constructs tumor immune privileged areas to induce immune evasion behavior of tumor cells. Here, we summarize the respective mechanisms of action played by different Galectins in the process of immune escape from PDAC, focusing on the mechanism of action of Galectin-1. Galectins cause imbalance between tumor immunity and anti-tumor immunity by coordinating the function and number of immune cells, which leads to the development and progression of PDAC.

SUBMITTER: Jiang Z

PROVIDER: S-EPMC9688059 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Galectins Are Central Mediators of Immune Escape in Pancreatic Ductal Adenocarcinoma.

Jiang Zhengting Z Zhang Wenjie W Sha Gengyu G Wang Daorong D Tang Dong D

Cancers 20221108 22

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers and is highly immune tolerant. Although there is immune cell infiltration in PDAC tissues, most of the immune cells do not function properly and, therefore, the prognosis of PDAC is very poor. Galectins are carbohydrate-binding proteins that are intimately involved in the proliferation and metastasis of tumor cells and, in particular, play a crucial role in the immune evasion of tumor cells. Galectins induce abnormal funct ...[more]

PMID: 36428567

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Project description:BackgroundPancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies worldwide. Immune escape is considered to be a reason for immunotherapy failure in PDAC. In this study, we explored the correlation between immune escape-related genes and the prognosis of PDAC patients.Methods1163 PDAC patients from four public databases, including The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC), Array-express, and Gene Expression Omnibus (GEO), were included in our study. Cox regression analysis was used to identify the 182 immune genes which were significantly associated with overall survival (OS). And then we established an immune escape-related gene prognosis index (IEGPI) score using several datasets as the training cohort and validated it using the validation cohort. Kaplan-Meier (KM) and Cox regression analysis were used to detect the relationship of IEGPI score with OS. We further explored the relationship between the IEGPI and immune indexes. And the prediction value of response for immunotherapy in Tumor Immune Dysfunction and Exclusion (TIDE) dataset.ResultsWe establish an IEGPI score based on 27 immune escape genes which were significantly related to the prognosis of OS in PDAC patients. Patients in the high-IEGPI group had a significantly worse overall survival rate compared with that in the low-IEGPI groups by KM curves and cox-regression. 5 of the 32 cancer types in TCGA could be significantly distinguished in survival rates through the low- and high-IEGPI groups. Moreover, the correlation between the IEGPI score was negatively correlated with an immune score in several datasets. And higher IEGPI better recurrence-free survival (RFS) and OS in the patients after patients were treated with both PD-1 and CTLA4 in the public datasets (P<0.05). Intriguingly, by using RT-PCR, we verified that the gene of PTPN2, CEP55, and JAK2 were all higher in the BxPC-3 and PANC-1 than HPDE5 cells. Lastly, we found that the IEGPI score was higher in K-rasLSL.G12D/+, p53LSL.R172H/+, Pdx1Cre (KPC) mice model with anti-PD-L1 than that without anti-PD-L1.ConclusionUsing the immune escape-related genes, our study established and validated an IEGPI score in PDAC patients from the public dataset. IEGPI score has the potential to serve as a prognostic marker and as a tool for selecting tumor patients suitable for immunotherapy in clinical practice.

Project description:BackgroundThe peritumoral stroma is a hallmark of pancreatic ductal adenocarcinoma (PDA) with implications for disease development, progression and therapy resistance. We systematically investigated immune features of the stroma in PDA patients to identify markers of clinical importance and potential therapeutic targets.MethodsTissue and blood samples of 51 PDA patients with clinical and follow-up information were included. Laser Capture Microdissection allowed us to analyze the stromal compartment in particular. Systematic immunohistochemistry, followed by software-based image analysis were conducted. Also, multiplex cytokine analyses (including 50 immune-related molecules) were performed. Functional analyses were performed using patient-derived 3D bioprints. Clinical information was used for survival analyses. Intercompartmental IL9 and IL18 gradients were assessed in matched samples of tumor epithelium, stroma, and serum of patients. Serum levels were compared to an age-matched healthy control group.ResultsStromal IL9 and IL18 are significantly associated with patient survival. While IL9 is a prognostic favorable marker (p=0.041), IL18 associates with poor patient outcomes (p=0.030). IL9 correlates with an anti-tumoral cytokine network which connects regulation of T helper (Th) 9, Th1 and Th17 cells (all: p<0.05 and r>0.5). IL18 correlates with a Th1-type cytokine phenotype and stromal CXCL12 expression (all: p<0.05 and r>0.5). Further, IL18 associates with a higher level of exhausted T cells. Inhibition of IL18 results in diminished Th1- and Th2-type cytokines. Patients with high stromal IL9 expression have a tumor-to-stroma IL9 gradient directed towards the stroma (p=0.019). Low IL18 expression associates with a tumor-to-stroma IL18 gradient away from the stroma (p=0.007). PDA patients showed higher serum levels of IL9 than healthy controls while serum IL18 levels were significantly lower than in healthy individuals. The stromal immune cell composition is distinct from the tumor epithelium. Stromal density of FoxP3+ regulatory T cells showed a tendency towards improved patient survival (p=0.071).ConclusionAn unexpected high expression of the cytokines IL9 and IL18 at different ends is of significance in the stroma of PDA and relates to opposing patient outcomes. Sub-compartmental cytokine analyses highlight the importance of a differentiated gradient assessment. The findings suggest stromal IL9 and/or IL18 as markers for patient stratification and as potential therapeutic targets. Future steps include investigating e. g. the role of local microbiota as both cytokines are also regulated by microbial compositions.

Dataset Information

Galectins Are Central Mediators of Immune Escape in Pancreatic Ductal Adenocarcinoma.

Publications

Galectins Are Central Mediators of Immune Escape in Pancreatic Ductal Adenocarcinoma.

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