1. Therapeutic melanoma inhibition by local micelle-mediated cyclic nucleotide repression
- Author
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Kerstin Johann, Toszka Bohn, Alexander Birke, Henriette Jaurich, Matthias Klein, Tobias Bopp, Natascha Luther, Mark Helm, Christian Becker, Matthias Barz, Fatemeh Shahneh, and Verena Raker
- Subjects
Skin Neoplasms ,Receptor expression ,Melanoma, Experimental ,Gene Expression ,General Physics and Astronomy ,Injections, Intralesional ,T-Lymphocytes, Regulatory ,Mice ,chemistry.chemical_compound ,Cyclic AMP ,Tumor Microenvironment ,Myeloid Cells ,Receptors, Immunologic ,Melanoma ,Micelles ,Multidisciplinary ,Chemistry ,Esters ,Tumor Burden ,medicine.anatomical_structure ,Polyglutamic Acid ,Tumour immunology ,Female ,Adenylyl Cyclases ,Regulatory T cell ,Science ,Antineoplastic Agents ,Mice, Transgenic ,chemical and pharmacologic phenomena ,Cyclase ,Article ,General Biochemistry, Genetics and Molecular Biology ,Cyclic nucleotide ,Immune system ,Benzyl Compounds ,medicine ,Animals ,Humans ,Cyclic adenosine monophosphate ,Tumor microenvironment ,Sarcosine ,General Chemistry ,medicine.disease ,Immunity, Innate ,Mice, Inbred C57BL ,Interleukin 1 Receptor Antagonist Protein ,Adenylyl Cyclase Inhibitors ,Drug delivery ,Cancer research ,Tumor Escape ,Peptides - 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., The acidic tumour microenvironment in melanoma drives immune evasion by cAMP in tumor-infiltrating monocytes. Here, the authors show that the release of an adenylate cyclase inhibitor from micelles restores antitumor immunity and, when combined with regulatory T cell depletion, leads to remission of established B16-F10-OVA tumors.
- Published
- 2021