Entwicklung und Erprobung von Nanopartikeln zur Aufhebung der cAMP-vermittelten Immunsuppression beim malignen Melanom (SFB 1066, B08)

Basic data for this project

Description

Cyclic adenosine monophosphate (cAMP) serves cells of all life forms as a signaling messenger and to regulate gene expression. In previous work, we have shown that murine and human regulatory T cells (Treg) transfer cAMP to other immune cells to suppress their function (J Exp Med. 2007 Jun 11;204(6):1303-10, Blood. 2009 Aug 6;114(6):1263-9). Adjuvant immunotherapy of melanoma patients with interferon alpha disarms Treg by inhibiting their cAMP formation (Cancer Res. 2013 Sep 15;73(18):5647-56). Interestingly, as a result of their high glycolytic activity, melanomas acidify their environment by lactate, which causes an increase in cAMP concentration in monocytes, thereby inhibiting their activity against the tumor (Nat Immunol. 2018 Dec;19(12):1319-1329). We have developed nanoparticulate micelles as part of the DFG Collaborative Research Center SFB 1066 www.sfb1066.de-zusammen with colleagues in Chemistry and Immunology in Mainz- (Biomacromolecules. 2014 Feb 10;15(2):548-57) that release an inhibitor of cAMP formation in tumor tissue. Local application of such inhibitor-loaded particles suppresses melanoma growth through metabolic reprogramming of infiltrating immune cells (Nat Commun. 2021 Oct 13;12(1):5981. doi: 10.1038/s41467-021-26269-w). We are currently further improving the cAMP inhibitor particles to make them systemic and thus clinically applicable. At the same time, we are investigating the molecular basis of cAMP-mediated reprogramming of the immune system to identify alternative, cell-specific points of intervention.