A 15-Gene Immune, Stromal, and Proliferation Gene Signature that Significantly Associates with Poor Survival in Patients with Pancreatic Ductal Adenocarcinoma

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Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with dismal survival rates. Tumor microenvironment (TME), comprising of immune cells and cancer-associated fibroblasts, plays a key role in driving poor prognosis and resistance to chemotherapy. Herein, we aimed to identify a TME-associated, risk-stratification gene biomarker signature in PDAC. The initial biomarker discovery was performed in The Cancer Genome Atlas (TCGA, n=163) transcriptomic data. This was followed by independent validation of the gene signature in The International Cancer Genome Consortium (ICGC, n=95), E-MTAB-6134 (n=288), and GSE71729 (n=123) datasets for predicting overall survival (OS), and for its ability to detect poor molecular subtypes. Clinical validation and nomogram establishment was undertaken by performing multivariate cox regression analysis. Our biomarker discovery effort identified a 15-gene immune, stromal and proliferation (ISP) gene signature that significantly associated with poor OS (HR: 3.90, 95% CI, 2.36–6.41, p<0.0001). This signature also robustly predicted survival in 3 independent validation cohorts ICGC (HR:2.63 [1.56–4.41], p<0.0001), E-MTAB-6134 (HR:1.53 [1.14–2.04], p=0.004), and GSE71729 (HR:2.33 [1.49–3.63], p<0.0001). Interestingly, the ISP signature also permitted identification of poor molecular PDAC subtypes with excellent accuracy in all 4 cohorts; TCGA (AUC=0.94), ICGC (AUC=0.91), E-MTAB-6134 (AUC=0.80), and GSE71729 (AUC=0.83). The ISP-derived high-risk patients exhibited significantly poor OS in a clinical validation cohort (n=119; HR:2.62 [1.50–4.56], p=0.0004). A nomogram was established which included the ISP, CA19–9, T and N-stage for eventual clinical translation. We report a novel gene signature for risk-stratification and robust identification of PDAC patients with poor molecular subtypes.

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IL-1-induced JAK/STAT signaling is antagonized by TGF-beta to shape CAF heterogeneity in pancreatic ductal adenocarcinoma

Giulia Biffi, Tobiloba Oni, Benjamin Spielman … (2018)

Pancreatic ductal adenocarcinoma (PDAC) is poorly responsive to therapies and histologically contains a paucity of neoplastic cells embedded within a dense desmoplastic stroma. Within the stroma, cancer-associated fibroblasts (CAF) secrete tropic factors and extracellular matrix components, and have been implicated in PDAC progression and chemotherapy resistance. We recently identified two distinct CAF subtypes characterized by either myofibroblastic or inflammatory phenotypes; however, the mechanisms underlying their diversity and their roles in PDAC remain unknown. Here, we use organoid and mouse models to identify TGFβ and IL1 as tumor-secreted ligands that promote CAF heterogeneity. We show that IL1 induces LIF expression and downstream JAK/STAT activation to generate inflammatory CAFs and demonstrate that TGFβ antagonizes this process by downregulating IL1R1 expression and promoting differentiation into myofibroblasts. Our results provide a mechanism through which distinct fibroblast niches are established in the PDAC microenvironment and illuminate strategies to selectively target CAFs that support tumor growth. SIGNIFICANCE: Understanding the mechanisms that determine CAF heterogeneity in PDAC is a prerequisite for the rational development of approaches that selectively target tumor-promoting CAFs. Here, we identify an IL1-induced signaling cascade that leads to JAK/STAT activation and promotes an inflammatory CAF state, suggesting multiple strategies to target these cells in vivo. See related commentary by Ling and Chiao, p. 173.This article is highlighted in the In This Issue feature, p. 151.

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Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial.

M C Cripps, P Tarassoff, A Storniolo … (1997)

Most patients with advanced pancreas cancer experience pain and must limit their daily activities because of tumor-related symptoms. To date, no treatment has had a significant impact on the disease. In early studies with gemcitabine, patients with pancreas cancer experienced an improvement in disease-related symptoms. Based on those findings, a definitive trial was performed to assess the effectiveness of gemcitabine in patients with newly diagnosed advanced pancreas cancer.

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Regulatory T Cells in the Tumor Microenvironment and Cancer Progression: Role and Therapeutic Targeting

Belal Chaudhary, Eyad Elkord (2016)

Recent years have seen significant efforts in understanding and modulating the immune response in cancer. In this context, immunosuppressive cells, including regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), have come under intense investigation for their proposed roles in suppressing tumor-specific immune responses and establishing an immunosuppressive tumor microenvironment, thus enabling tumor immune evasion. Additionally, recent evidence indicates that Tregs comprise diverse and heterogeneous subsets; phenotypically and functionally distinct subsets of tumor-infiltrating Tregs could contribute differently to cancer prognosis and clinical outcomes. Understanding Treg biology in the setting of cancer, and specifically the tumor microenvironment, is important for designing effective cancer therapies. In this review, we critically examine the role of Tregs in the tumor microenvironment and in cancer progression focusing on human studies. We also discuss the impact of current therapeutic modalities on Treg biology and the therapeutic opportunities for targeting Tregs to enhance anti-tumor immune responses and clinical benefits.