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 () and Christian Becker ()
Additional contact information
Kerstin Johann: Johannes Gutenberg University
Toszka Bohn: Johannes Gutenberg University
Fatemeh Shahneh: Johannes Gutenberg University
Natascha Luther: Johannes Gutenberg University
Alexander Birke: Johannes Gutenberg University
Henriette Jaurich: Johannes Gutenberg University
Mark Helm: Johannes Gutenberg University
Matthias Klein: Johannes Gutenberg University
Verena K. Raker: Johannes Gutenberg University
Tobias Bopp: Johannes Gutenberg University
Matthias Barz: Johannes Gutenberg University
Christian Becker: Johannes Gutenberg University

Nature Communications, 2021, vol. 12, issue 1, 1-9

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-26269-w

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