Muc1/sec: A Secreted Alternative Splice Variant Of Muc1 That Promotes Tumor Immunity

Human MUC1/sec is a secreted form of the glycoprotein mucin 1 (MUC1). In order to characterize the role that MUC1 and MUC1/sec have in tumor progression, these genes were expressed in DA-3 mammary tumor cells. DA-3 cells and DA-3 cells expressing the full length transmembrane form of MUC1 (DA-3/TM) grow with similar kinetics in BALB/c mice. Surprisingly, DA-3 cells expressing and secreting MUC1/sec (DA-3/sec) fail to form tumors in vivo. The mechanism of rejection was evaluated using mice deficient in constituents of the immune system. All mice lacking IFN-gamma, NK, NKT, or macrophages formed DA-3/sec tumors that regressed shortly after implantation. However, progressively growing DA-3/sec tumors developed in mice devoid of T lymphocytes. The importance of T lymphocytes in the rejection of DA-3/sec tumors was further supported by detection of DA-3 specific CTL in mice challenged with the DA3/sec tumor. Recruitment of appropriate antigen presenting and effector cells is an important first step in the tumor clearance. Indeed, DA-3/sec cells or cell supernatants recruited 3--4 times as many macrophages as DA-3/TM cells in vivo, suggesting that a secreted chemotactic product is produced from DA-3/sec cells. RNA and protein analysis of DA-3/sec cells revealed that several genes are up-regulated by MUC1/sec expression, including monocyte chemotactic protein 1 (MCP-1).Further investigations into the production of chemokines in DA-3/sec cells revealed that MUC1/sec directly controls MCP-1 production. Incubation of DA-3/sec cells with a MUC1/sec-specific antibody reduced MCP-1 protein levels, and conversely, incubation of DA-3/sec cells with a MUC1/sec-derived peptide increased MCP-1 levels. MCP-1 regulation is dependent on several signaling pathways, including the p38MAP kinase and protein kinase C pathway. Using inhibitors of these pathways, MCP-1 production was abrogated in DA-3/sec cells, suggesting MUC1/sec may be activating MCP-1 through these signaling networks. Overall, these results point to a novel function for the secreted isoform of mucin 1, MUC1/sec, in the stimulation of both innate and T cell immunity in the prevention of tumor cell growth in vivo