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Therapeutic melanoma inhibition by local micelle-mediated cyclic nucleotide repression

Author

Listed:
  • 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
    Johannes Gutenberg University)

  • Mark Helm

    (Johannes Gutenberg University)

  • Matthias Klein

    (Johannes Gutenberg University)

  • Verena K. Raker

    (Johannes Gutenberg University
    Westfälische Wilhelms-University)

  • Tobias Bopp

    (Johannes Gutenberg University)

  • Matthias Barz

    (Johannes Gutenberg University
    Leiden Academic Center for Drug Research (LACDR))

  • Christian Becker

    (Johannes Gutenberg University
    Westfälische Wilhelms-University)

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.

Suggested Citation

  • 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, 2021. "Therapeutic melanoma inhibition by local micelle-mediated cyclic nucleotide repression," Nature Communications, Nature, vol. 12(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26269-w
    DOI: 10.1038/s41467-021-26269-w
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    References listed on IDEAS

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    1. Marc A. Gavin & Jeffrey P. Rasmussen & Jason D. Fontenot & Valeria Vasta & Vincent C. Manganiello & Joseph A. Beavo & Alexander Y. Rudensky, 2007. "Foxp3-dependent programme of regulatory T-cell differentiation," Nature, Nature, vol. 445(7129), pages 771-775, February.
    2. Antoni Ribas & Paul C. Tumeh, 2012. "Tumours switch to resist," Nature, Nature, vol. 490(7420), pages 347-348, October.
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