Abstract IA7: Innate immune signaling in the pancreatic tumor microenvironment
Authors: Miller George 
Published: October 2015

Abstract
Pancreatic ductal adenocarcinoma (PDA) is a devastating disease in which mortality rates approach incidence rates. Invasive PDA is necessarily preceded by a robust intra-pancreatic inflammatory infiltrate which participates in intimate cross-talk with the at-risk or transformed epithelial compartment. However, specific peri-pancreatic inflammatory entities can have widely divergent effects on tumorigenesis by either combating transformation via innate or antigen-restricted tumoricidal immune responses or by promoting tumor growth by providing nutrient sustenance to tumors via the release of tumor-promoting cytokines or growth factors. Elements of the adaptive immune system have a central role in modulating tumorigenesis. We recently reported that antigen-restricted Th2 cells promote pancreatic cancer progression in mice. Accordingly, intratumoral CD4+ Th2 cell infiltrates correlate with reduced survival in human pancreatic cancer. CD4+CD25+Foxp3+ regulatory T cells also facilitate tumor immune escape in murine models and human pancreatic adenocarcinoma. Conversely, CD8+ T cells mediate tumor protection. Innate inflammatory cells also play a vital role in pancreatic tumorigenesis. We reported that immature myeloid cells proliferate in the transformed pancreas and in the pre-metastatic niche and can negate adaptive CD8+ T cells mediated anti-tumor immunity leading to accelerated cancer growth within the pancreas and in the metastatic liver. Similarly, dendritic cells can also promote inflammation and tumorigenesis within the pancreas by inducing the proliferation of Th2 cells. Innate immune receptors and specifically pattern recognition receptors link environmental stimuli to innate immune responses and inflammation. Toll-like receptors (TLRs) are the most well-studied family of pattern recognition receptors. TLRs bind specific molecular motifs derived from microbes, collectively denoted pathogen associated molecular patterns (PAMPs) and thus have a critical role in our capacity to mount an immune responses to invading micro-organisms. However, in addition to binding PAMPs, TLRs are activated by ligating non-pathogenic ‘danger molecules’ which include by-products of inflammatory injury and cellular necrosis, collectively denoted damage associated molecular patterns (DAMPs). Our preliminary work found that the pancreatic tumor microenvironment is rife with DAMPs including HMGB-1 and S100A9. We also found that gut-derived pathogens and PAMPs can access the pancreas. Moreover, Toll-like receptor expression is upregulated on transformed pancreatic ductal epithelial cells, peri-tumoral inflammatory cells, and pancreatic stellate cells in PDA. Based on these data we postulated the ligation of TLRs by peri-pancreatic DAMPs or PAMPs may induce tumor-promoting inflammation. We found that ligation of TLR4, TLR7, or TLR9 accelerates pancreatic cancer progression in an NF-κB and MAP Kinase dependent manner. TLR ligation resulted in activation of Notch and STAT3 signaling mechanisms in both epithelia and stromal compartments. Moreover, blockade of selective TLRs was protective against PDA development. Our work suggests that targeting TLRs may be an attractive strategy to prevent tumorigenesis in at-risk patients or to treat early pancreatic neoplasia.
Citation Format: George Miller. Innate immune signaling in the pancreatic tumor microenvironment. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr IA7.