Leflunomide Changes the Tumor Immune Microenvironment and Mitigates Pancreatic Cancer Growth in an Immunocompetent Mouse Model

Abstract Background: Increasing evidence suggested that the critical roles for lncRNAs in the maintenance of genomic stability. However, the identification of genomic instability related lncRNA signature (GILncSig) and their clinical significance in tumor immune microenvironment of pancreatic cancer remain largely unexplored.Methods: In the present study, a systematic analysis of lncRNA expression profiles and somatic mutation profiles was performed in pancreatic cancer patients from TCGA. We performed co-expression network and Gene Ontology (GO) enrichment analyses to determine the potential functions and pathways involved in lncRNAs are associated with genomic instability. We then development a risk score model to describe the characteristics of the model and verify its prediction accuracy. ESTIMATE algorithm, single-sample gene set enrichment analysis (ssGSEA), and CIBERSORT analysis were employed to reveal the characteristics of tumor immune microenvironment in pancreatic cancer. The correlation of risk signature with immune infiltration and immune checkpoint blockade (ICB) therapy was analyzed. Results: We identified 206 GILncSig, of which five were screened to develop a prognostic GInLncSig model. Multivariate Cox regression analysis and stratified analysis revealed that the prognostic value of the GILncSig was independent of other clinical variables. ROC analysis suggested that GILncSig is better than the existing lncRNA-related signatures in predicting survival. Additionally, the prognostic performance of the GILncSig was also found to be favorable in patients carrying wild-type KRAS, TP53 and SMAD4. Besides, a nomogram exhibited appreciable reliability for clinical application in predicting the prognosis of patients. Finally, the risk score significantly correlated with immune score, immune-related signature, infiltrating immune cells (i.e. B cells, etc.), and ICB key molecules (i.e. CTLA4, etc.). Conclusion: In summary, the GILncSig identified by us may have crucial role in immune cell infiltration，immunotherapy and important indicator for clinical stratification management and therapy decisions for pancreatic cancer patients.

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Established fibrous peritoneal metastasis in an immunocompetent mouse model similar to clinical immune microenvironment of gastric cancer

10.21203/rs.3.rs-41049/v3 ◽

2020 ◽

Author(s):

Daisuke Fujimori ◽

Jun Kinoshita ◽

Takahisa Yamaguchi ◽

Yusuke Nakamura ◽

Katsuya Gunjigake ◽

...

Keyword(s):

Gastric Cancer ◽

Mouse Model ◽

Cell Line ◽

Peritoneal Metastasis ◽

Treatment Strategies ◽

M2 Macrophages ◽

Immunocompetent Mouse ◽

Immune Microenvironment ◽

Fibrous Stroma ◽

Immunocompetent Mice

Abstract Background Peritoneal metastasis (PM) in gastric cancer (GC) is characterized by diffusely infiltrating and proliferating cancer cells accompanied by extensive stromal fibrosis in the peritoneal space. The prognosis of GC with PM is still poor regardless of the various current treatments. In order to elucidate the cause of difficulties in PM treatment, we compared the tumor immune microenvironment (TME) in primary and PM lesions in GC. In addition, a PM model with fibrous stroma was constructed using immunocompetent mice to determine whether its TME was similar to that in patients. MethodsImmuno-histochemical analyses of infiltrating immune cells were performed in paired primary and PM lesions from 28 patients with GC. A C57BL/6J mouse model with PM was established using the mouse GC cell line YTN16 either with or without co-inoculation of mouse myofibroblast cell line LmcMF with a-SMA expression. The resected PM from each mouse model was analyzed the immunocompetent cells using immunohistochemistry.ResultsThe number of CD8+ cells was significantly lower in PM lesions than in primary lesions (P<0.01). Conversely, the number of CD163+ cells (M2 macrophages) was significantly higher in PM lesions than in primary lesions (P=0.016). Azan staining revealed that YTN16 and LmcMF co-inoculated tumors were more fibrous than tumor with YTN16 alone (P<0.05). Co-inoculated fibrous tumor also showed an invasive growth pattern and higher progression than tumor with YTN16 alone (P=0.045). Additionally, YTN16 and LmcMF co-inoculated tumors showed lower infiltration of CD8+ cells and higher infiltration of M2 macrophages than tumors with YTN16 alone (P<0.05, P<0.05). These results indicate that LmcMF plays as cancer-associated fibroblasts (CAFs) by crosstalk with YTN16 and CAFs contribute tumor progression, invasion, fibrosis, and immune suppression.ConclusionsThis model is the first immunocompetent mouse model similar to TME of human clinical PM with fibrosis. By using this model, new treatment strategies for PM, such as anti-CAFs therapies, may be developed.

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