Abstract
SummaryRegulatory T (Treg) cell infiltration constitutes a prominent feature of pancreatic ductal adenocarcinoma (PDA). However, the immunomodulatory function of Treg cells in PDA is poorly understood. Here, we demonstrate that Treg cell ablation is sufficient to evoke effective anti-tumor immune response in early and advanced pancreatic tumorigenesis in mice. This response is dependent on interferon-γ (IFN-γ)-producing cytotoxic CD8+ T cells. We show that Treg cells engage in extended interactions with tumor-associated CD11c+ dendritic cells (DCs) and restrain their immunogenic function by suppressing the expression of costimulatory ligands necessary for CD8+ T cell activation. Consequently, tumor-associated CD8+ T cells fail to display effector activities when Treg cell ablation is combined with DC depletion. We propose that tumor-infiltrating Treg cells can promote immune tolerance by suppressing tumor-associated DC immunogenicity. The therapeutic manipulation of this axis might provide an effective approach for the targeting of PDA.
Highlights
Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal human malignancies (Ryan et al, 2014)
Treg Cells Are Required for Pancreatic Tumorigenesis To discern the functional role of Treg cells in the development of pancreatic neoplasia, we employed an orthotopic implantation model in which primary KrasG12D-expressing pancreatic ductal epithelial cells (KrasG12D-PDECs) labeled with GFP (GFP-KrasG12D-PDECs) are injected into the pancreata of syngeneic C57BL/6 wild-type (WT) mice (Pylayeva-Gupta et al, 2013)
This model histologically recapitulates the pre-invasive stages of pancreatic intraepithelial neoplasia (PanIN) development and induces an intra-pancreatic immune response similar to that observed in the genetically engineered p48-Cre;KrasG12D (KC) mouse model of pancreatic neoplasia (Clark et al, 2007; Pylayeva-Gupta et al, 2012)
Summary
Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal human malignancies (Ryan et al, 2014). Murine models of oncogenic Ras-driven PDA recapitulate many of these immune signatures (Bayne et al, 2012; Clark et al, 2007; Daley et al, 2016). In PDA, the accumulation of Treg cells in the tumor microenvironment occurs during the preinvasive stage of the disease (Clark et al, 2007; Hiraoka et al, 2006). A high frequency of Treg cells in the pre-neoplastic pancreas is associated with poor prognosis and reduced survival in murine and human PDA (Hiraoka et al, 2006; Tang et al, 2014). Treg cell depletion in combination with conventional PDA treatment strategies has been shown to enhance cancer-specific T cell activation in preclinical studies (Keenan et al, 2014; Leao et al, 2008)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
