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.
© 2021. The Author(s).
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenylyl Cyclase Inhibitors / chemical synthesis
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Adenylyl Cyclase Inhibitors / pharmacology*
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Adenylyl Cyclases / genetics*
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Adenylyl Cyclases / immunology
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Animals
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / pharmacology*
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Benzyl Compounds / chemistry
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Cyclic AMP / antagonists & inhibitors*
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Cyclic AMP / immunology
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Cyclic AMP / metabolism
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Esters
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Female
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Gene Expression
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Humans
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Immunity, Innate / drug effects
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Injections, Intralesional
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Interleukin 1 Receptor Antagonist Protein / genetics
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Interleukin 1 Receptor Antagonist Protein / immunology
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Melanoma, Experimental / drug therapy*
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Melanoma, Experimental / genetics
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Melanoma, Experimental / immunology
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Melanoma, Experimental / pathology
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Micelles
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Myeloid Cells / drug effects
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Myeloid Cells / immunology
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Myeloid Cells / pathology
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Peptides / chemistry
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Polyglutamic Acid / chemistry
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Receptors, Immunologic / antagonists & inhibitors
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Receptors, Immunologic / genetics
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Receptors, Immunologic / immunology
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Sarcosine / analogs & derivatives
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Sarcosine / chemistry
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Skin Neoplasms / drug therapy*
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Skin Neoplasms / genetics
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Skin Neoplasms / immunology
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Skin Neoplasms / pathology
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T-Lymphocytes, Regulatory / drug effects
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T-Lymphocytes, Regulatory / immunology
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T-Lymphocytes, Regulatory / pathology
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Tumor Burden / drug effects
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Tumor Escape / drug effects
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Tumor Microenvironment / drug effects
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Tumor Microenvironment / genetics
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Tumor Microenvironment / immunology
Substances
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Adenylyl Cyclase Inhibitors
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Antineoplastic Agents
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Benzyl Compounds
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Esters
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Il1rn protein, mouse
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Interleukin 1 Receptor Antagonist Protein
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Micelles
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Peptides
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Receptors, Immunologic
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T cell Ig and ITIM domain protein, mouse
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Polyglutamic Acid
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polysarcosine
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Cyclic AMP
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Adenylyl Cyclases
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Sarcosine
Associated data
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figshare/10.6084/m9.figshare.16419204.v1