The pancreatic ductal adenocarcinoma (PDAC) microenvironment is a diverse and complex milieu of immune, stromal, and tumor cells and is characterized by a dense stroma, which mediates the interaction between the tumor and the immune system within the tumor microenvironment (TME). The interaction between stromal and tumor cells signals and shapes the immune infiltration of TME. The desmoplastic compartment contains infiltrated immune cells including tumor-associated macrophages (TAMs) and large numbers of fibroblasts/myofibroblasts dominated by pancreatic stellate cells (PSCs) which contribute to fibrosis. The highly fibrotic stroma with its extensive infiltration of immunosuppressive cells forms the major component of the pro-tumorigenic microenvironment (Laklai et al. Nat Med 22:497-505, 2016, Zhu et al. Cancer Res 74:5057-5069, 2014) provides a barrier to the delivery of cytotoxic agents and limits T-cell access to tumor cells (Feig et al. Proc Natl Acad Sci USA 110:20212-20217, 2013, Provenzano et al Cancer Cell 21:418-429, 2012). Activated PSCs reduced infiltration of cytotoxic T cells to the juxtatumoral stroma (immediately adjacent to the tumor epithelial cells) of PDAC (Ene-Obong et al. Gastroenterology 145:1121-1132, 2013). M1 macrophages activate an immune response against tumor, but M2 macrophages are involved in immunosuppression promoting tumor progression (Noy and Pollard Immunity 41:49-61, 2014, Ruffell et al. Trends Immunol 33:119-126, 2012). The desmoplastic stroma is reported to protect tumor cells against chemotherapies, promoting their proliferation and migration. However, experimental depletion of the desmoplastic stroma has led to more aggressive cancers in animal studies (Nielsen et al. World J Gastroenterol 22:2678-2700, 2016). Hence reprogramming rather than simple depletion of the PDAC stroma has the potential for developing new therapeutic strategies for PC treatment. Modulation of PSCs/fibrosis and immune infiltration/inflammation composes the major aspects of TME reprogramming.
Keywords: Alpha-smooth muscle actin (α-SMA); Collagens; Cytotoxic T cells; Extracellular matrix (ECM); Gemcitabine; Hypoxia; Hypoxia-inducible factors (HIFs); Immune checkpoint proteins; Myeloid-derived suppressor cells (MDSCs); Pancreatic ductal adenocarcinoma (PDAC); Pancreatic stellate cells (PSCs); Tumor immune response; Tumor infiltrating lymphocytes (TILs); Tumor microenvironment (TME); Tumor-associated macrophages (TAMs).