Abstract B070: TGFB2 mRNA levels prognostically interact with Interferon-alpha receptor activation of IRF9 and IFI27, and makers for tumor-associated macrophages impacting overall survival in PDAC

Abstract

Abstract Background: The treatment of pancreatic ductal adenocarcinoma (PDAC) is an unmet challenge, with the median overall survival rate remaining less than a year, even with the use of FOLFIRINOX-based therapies. Methods: In this study, we analyzed archived macrophage- associated mRNA expression using datasets deposited in the UCSC Xena web platform to compare normal pancreatic tissue and PDAC tumor samples. We also utilized TCGA datasets deposited in cBioportal (https://www.cbioportal.org/study/summary?id=paad_tcga_pan_can_atlas) and KMplotter (http://kmplot.com/analysis/index.php?p=service&cancer=pancancer_rnaseq) to relate mRNA expression levels to overall survival outcomes. The prognostic impact of TGFB2 mRNA expression levels was determined by comparing patients expressing high versus low levels of TGFB2 (50th percentile cut-off) in low macrophage TME. Results: The TGFB2 gene exhibited low mRNA expression levels in normal tissue, with less than one TPM, while, in tumor tissue, TGFB2 expression levels exhibited a 7.9-fold increase in mRNA expression relative to normal tissue (P < 0.0001). Interferon Alpha Inducible Protein 27 (IFI27), the downstream product of Interferon regulatory factor 9 (IRF9) and Signal transducer and activator of transcription 1 (STAT1) transcriptional activation by Interferon alpha/beta receptor 1 (IFNAR1) exhibited a significant 66.3-fold increase in expression in tumor tissue compared to normal tissue (P < 0.0001). The statistical contrast between the expression of IRF9 mRNA also displayed a significant (P<0.0001) 4.2-fold increase in mRNA expression levels. These increased levels of mRNA expression were found to be prognostically significant, whereby patients with high expression levels of either TGFB2, IRF9, or IFI27 showed median OS times ranging from 16 to 20 months (P<0.01 compared to 72 months for patients with low levels of expression for both TGFB2 and either IRF9 or IFI27). In TME with low macrophage levels, patients with high levels of TGFB2 mRNA exhibited significantly shorter OS outcomes than patients with low TGFB2 mRNA levels (Median OS of 72.2 versus 15.3 months, P<0.0001). Furthermore, expression of TGFB2 mRNA and TAM markers exhibited TGFB2 prognostic impact independent of 17 TAM markers suggested by multivariate Cox regression models. Conclusions: The results of our study suggest that a combination of pharmacological tools can be used in treating PDAC patients, targeting both TGFB2 and the components of the type-I interferon signaling pathway to improve OS outcomes. TGFB2 expression impacts OS independent of TAM markers, but the expression of TAM markers impacts the prognostic effect of TGFB2 mRNA expression. Citation Format: Sanjive Qazi, Wen-Han Chang, Cynthia Lee, Vuong Trieu. TGFB2 mRNA levels prognostically interact with Interferon-alpha receptor activation of IRF9 and IFI27, and makers for tumor-associated macrophages impacting overall survival in PDAC [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B070.