Role of L1CAM in migration and effector function of regulatory T cells in pancreatic ductal adenocarcinoma and its potential for improved therapy
Final Report Abstract
The adhesion molecule L1CAM (L1, CD171) is overexpressed in highly malignant pancreatic ductal adenocarcinoma (PDAC) and we already demonstrated an important role for L1CAM in cell migration and apoptosis resistance of PDAC cells. PDAC is characterized by a profound stromal compartment comprising a plethora of immune cells, e.g regulatory T-cells (Tregs) whose increased prevalence has been associated with short survival. However, the mechanisms underlying enrichment of Tregs in the tumor as well as their direct protumorigenic effects have been poorly understood, in particular in the highly malignant PDAC. Thus, the project aimed to investigate how L1CAM affects enrichment and effector function of Tregs and vice versa how Tregs contribute to malignant transformation of PDAC. Based on the data generated within the project, the following model can be envisaged on the fatal alliance of T cells and pancreatic ductal epithelial/tumor cells that promotes inflammation associated PDAC development: Upon pancreatic inflammation (e.g. during chronic pancreatitis or upon smouldering inflammation induced by smoking, alcohol or diabetes mellitus), CD4 + T cells (most likely T effector cells, Teffs) infiltrate the pancreatic tissue where they come in contact with the pancreatic ductal epithelium. By releasing inflammatory cytokines such as TNF-α, IL-1β, T cells induce EMT associated alterations along with enhanced L1CAM expression in pancreatic ductal epithelium. Then, on the one hand, L1CAM expression increases the tumorigenecity, invasive behavior and apoptosis resistance of epithelial cells and later on tumor cells. On the other hand, L1CAM contributes to the enrichment of immunosuppressive T cells by promoting migration/infiltration of Tregs into the pancreas, impairing proliferation of Teffs and favoring the generation of immunosuppressive CD4+CD25-CD69+ T-cells. In particular, the latter Treg population may contribute to immune evasion quite early during PDAC development because these cells are highly abundant already in CP tissues. Besides demonstrating a novel function of L1CAM in the generation of an immunosuppressive microenvironment, this study provides novel insights into the plasticity of T cells, particularly Tregs, in human PDAC. Furthermore, it suggests that the number and phenotypes of immunosuppressive T cells within tumors might be much higher and more complex as assumed so far. This knowledge is pivotal for the development of therapeutic strategies to efficiently target this potent immunological barrier in highly malignant PDAC. Given the fundamental role of L1CAM in the mediation of chemoresistance, cell invasion and metastasis as well as in immunoregulation, L1CAM have great potential as target in PDAC therapy.
Publications
- (2012) Combined treatment of L1CAM antibodies and cytostatic drugs improve the therapeutic response of pancreatic and ovarian carcinoma. Cancer Lett 319(1): 66- 82
Schäfer H, Dieckmann C, Korniienko O, Moldenhauer G, Kiefel H, Salnikov A, Krüger A, Altevogt P, Sebens S
(See online at https://doi.org/10.1016/j.canlet.2011.12.035) - (2012). EMT–associated up-regulation of L1CAM in carcinoma cells reveals further insight into L1CAM-integrin signalling and NF-κB activation. Carcinogenesis 33(10):1919-29
Kiefel H, Bondong S, Pfeifer M, Erbe-Hoffmann N, Schäfer H, Sebens S, Altevogt P
- (2012). Myofibroblast-induced tumorigenicity of pancreatic ductal epithelial cells is L1CAM-dependent. Carcinogenesis, 33(1): 84-93
Schäfer H, Geismann C, Heneweer C, Egberts J-H, Korniienko O, Moldenhauer G, Bachem MG, Kalthoff H, Altevogt P, Sebens S
(See online at https://doi.org/10.1093/carcin/bgr262) - (2014) L1CAM promotes enrichment of immunosuppressive T cells in human pancreatic cancer correlating with malignant progression. Mol Oncol. 8(5):982-97
Grage-Griebenow E, Jerg E, Gorys A, Wicklein D, Wesch D, Freitag-Wolf S, Goebel L, Vogel I, Becker T, Ebsen M, Röcken C, Altevogt P, Schumacher U, Schäfer H, Sebens S
(See online at https://doi.org/10.1016/j.molonc.2014.03.001) - (2014). Comparative characterization of stroma cells and ductal epithelium in chronic pancreatitis and pancreatic ductal adenocarcinoma. Plos One 9(5):e94357
Helm O, Mennrich R, Petrick D, Goebel L, Freitag-Wolf S, Röder C, Kalthoff H, Röcken C, Sipos B, Kabelitz D, Schäfer H, Oberg H-H, Wesch D, Sebens S
(See online at https://doi.org/10.1371/journal.pone.0094357) - (2014). The fatal alliance of tumor and T cells: How pancreatic tumor cells gather immunosuppressive T cells. OncoImmunology 3:e29382
Grage-Griebenow E, Schäfer H, Sebens S
(See online at https://doi.org/10.4161/onci.29382) - (2015). CD4+ T cells potently induce epithelial-mesenchymal-transition in premalignant and malignant pancreatic ductal epithelial cells - novel implications of CD4+ T cells in pancreatic cancer development. OncoImmunology, 4:4 (PDF: 16 S.)
Goebel L, Grage-Griebenow E, Gorys A, Helm O, Genrich G, Lenk L, Wesch D, Ungefroren H; Freitag-Wolf S, Sipos B, Röcken C, Schäfer H, Sebens S
(See online at https://doi.org/10.1080/2162402X.2014.1000083)
