Therapeutic melanoma inhibition by local micelle-mediated cyclic nucleotide repression

Kerstin Johann,Verena K Raker,Matthias Barz,Matthias Klein,Fatemeh Shahneh,Henriette Jaurich,Tobias Bopp,Alexander Birke,Toszka Bohn,Mark Helm,Natascha Luther,Christian Becker

doi:10.1038/s41467-021-26269-w

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.

Highlights

The acidic tumor microenvironment in melanoma drives immune evasion by up-regulating cyclic adenosine monophosphate in tumor-infiltrating monocytes
We show that the nucleotide cyclase inhibitor MDL-12,330A20 can be incorporated into polypept(o)ide micelles[21,22,23,24,25,26,27,28] and is continuously released from them locally in melanomas
The block copolymer displayed a molecular weight of 32.5 kg/mol and dispersity of 1.15 marking controlled polymerization (Supplementary Fig. 1)

Summary

Introduction

The acidic tumor microenvironment in melanoma drives immune evasion by up-regulating cyclic adenosine monophosphate (cAMP) in tumor-infiltrating monocytes. In contrast to the free drug, MDL-loaded micelles are non-toxic, suppress cAMP formation in tumor tissue and melanoma growth efficiently. To prepare MDL-loaded micelles, amphiphilic block copolypept(o)ides were subjected to dual centrifugation (cartoon Fig. 1)[30] in the presence of one equivalent of the drug and subsequently purified by spin filtration.

Results

Conclusion