Therapeutic melanoma inhibition by local micelle-mediated cyclic nucleotide repression
Kerstin Johann, Toszka Bohn, Fatemeh Shahneh, Natascha Luther, Alexander Birke, Henriette Jaurich, Mark Helm, Matthias Klein, Verena K. Raker, Tobias Bopp, Matthias Barz, Christian Becker
The acidic tumor microenvironment in melanoma drives immune evasion by up-regulating cyclic adenosine monophosphate (cAMP) in tumor-infiltrating monocytes. Here we show that the release of non-toxic concentrations of an adenylate cyclase (AC) inhibitor from poly(sarcosine)-block-poly(L-glutamic acid γ-benzyl ester) (polypept(o)id) copolymer micelles restores antitumor immunity. In combination with selective, non-therapeutic regulatory T cell depletion, AC inhibitor micelles achieve a complete remission of established B16-F10-OVA tumors. Single-cell sequencing of melanoma-infiltrating immune cells shows that AC inhibitor micelles reduce the number of anti-inflammatory myeloid cells and checkpoint receptor expression on T cells. AC inhibitor micelles thus represent an immunotherapeutic measure to counteract melanoma immune escape.
cAMP, micelles, melanoma, T cell