T lymphocytes in pancreatic cancer: Evaluation of the role of alternative p38 pathway in an in vivo model
Final Report Abstract
Pancreatic cancer is a highly aggressive disease with a poor prognosis, characterized by a distinctive inflammatory microenvironment. The infiltrating cells (e.g. T cells, macrophages, neutrophils etc.) often fail to eliminate the tumor but instead promote its progression by secretion of tumor-promoting cytokines and chemokines. Therefore it is worth considering that also signaling pathways in the host micromilieu offer therapeutic targeting points. This project focused on the role of a special signaling cascade, the so-called alternative p38 signaling pathway, which is present in tumor-infiltrating T cells. With different mouse models we could clearly show that p38 is alternatively activated in tumor- or pancreas-infiltrating T cells and controls pro-tumorigenic cytokine secretion, e.g. of TNFα and IL-17A. These cytokines could be shown to mediate aggressive tumor-progression. Therefore the specific treatment of this pathway could be beneficial for patients suffering from PDAC. In cooperation with another postdoc who created and characterized a specific inhibitor of the alternative p38 pathway, different pancreatic cancer mouse models were treated with this compound. We could clearly see a therapeutical benefit (smaller tumors, fewer precursor lesions, less protumorigenic cytokines from TIL, less protumorigenic chemokines in pancreatic cells, less neoangiogensis). Because in patients with pancreatic cancer a high degree of alternative p38 activation is associated with increased protumorigenic cytokine production, increased angiogenesis, and poor survival, the peptide inhibitor may represent a novel immunotherapeutic approach for PDAC, which might be worth testing for clinical practice.
Publications
- Counter-regulation of T cell effector function by differentialy activated p38. J Exp Med 2014
Alam MS, Gaida MM, Ogawa Y, Kolios AG, Lasitschka F, Ashwell JD
(See online at https://doi.org/10.1084/jem.20131917) - Selective inhibition of the p38 alternative activation pathway in infiltrating T cells inhibits pancreatic cancer progression. Nature Medicine volume 21, pages 1337–1343 (2015)
Alam MS, Gaida MM, Bergmann F, Lasitschka F,Giese T, Giese NA, Hackert T, Ulf Hinz, S Perwez Hussain, Serguei V Kozlov, Ashwell JD
(See online at https://doi.org/10.1038/nm.3957)
