Endosomolytic Polymersomes Increase the Activity of Cyclic Dinucleotide STING Agonists to Enhance Cancer Immunotherapy

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Abstract

Cyclic dinucleotide (CDN) agonists of stimulator of interferon genes (STING) are a promising class of immunotherapeutic that activate innate immunity to increase tumor immunogenicity. However, the efficacy of CDNs is limited by drug delivery barriers, including poor cellular targeting, rapid clearance, and inefficient transport to the cytosol where STING is localized. Here we describe STING-activating nanoparticles (STING-NPs), rationally designed polymersomes for enhanced cytosolic delivery of the endogenous CDN ligand for STING, 2’3’ cyclic guanosine monophosphate-adenosine monophosphate (cGAMP). STING-NPs increase the biological potency of cGAMP, enhance STING signaling in the tumour microenvironment and sentinel lymph node, and convert immunosuppressive tumours to immunogenic, tumouricidal microenvironments. This leads to enhanced therapeutic efficacy of cGAMP, inhibition of tumour growth, increased rates of long-term survival, improved response to immune checkpoint blockade, and induction of immunological memory that protects against tumour rechallenge. We validate STING-NPs in freshly isolated human melanoma tissue, highlighting their potential to improve clinical outcomes of immunotherapy.

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Most cited references 26

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STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors.

Seng-Ryong Woo, Mercedes Fuertes, Leticia Corrales … (2014)

Spontaneous T cell responses against tumors occur frequently and have prognostic value in patients. The mechanism of innate immune sensing of immunogenic tumors leading to adaptive T cell responses remains undefined, although type I interferons (IFNs) are implicated in this process. We found that spontaneous CD8(+) T cell priming against tumors was defective in mice lacking stimulator of interferon genes complex (STING), but not other innate signaling pathways, suggesting involvement of a cytosolic DNA sensing pathway. In vitro, IFN-? production and dendritic cell activation were triggered by tumor-cell-derived DNA, via cyclic-GMP-AMP synthase (cGAS), STING, and interferon regulatory factor 3 (IRF3). In the tumor microenvironment in vivo, tumor cell DNA was detected within host antigen-presenting cells, which correlated with STING pathway activation and IFN-? production. Our results demonstrate that a major mechanism for innate immune sensing of cancer occurs via the host STING pathway, with major implications for cancer immunotherapy. Copyright © 2014 Elsevier Inc. All rights reserved.

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Chemokine expression in melanoma metastases associated with CD8+ T-cell recruitment.

Helena Harlin, Yuru Meng, Amy C Peterson … (2009)

Despite the frequent detection of circulating tumor antigen-specific T cells, either spontaneously or following active immunization or adoptive transfer, immune-mediated cancer regression occurs only in the minority of patients. One theoretical rate-limiting step is whether effector T cells successfully migrate into metastatic tumor sites. Affymetrix gene expression profiling done on a series of metastatic melanoma biopsies revealed a major segregation of samples based on the presence or absence of T-cell-associated transcripts. The presence of lymphocytes correlated with the expression of defined chemokine genes. A subset of six chemokines (CCL2, CCL3, CCL4, CCL5, CXCL9, and CXCL10) was confirmed by protein array and/or quantitative reverse transcription-PCR to be preferentially expressed in tumors that contained T cells. Corresponding chemokine receptors were found to be up-regulated on human CD8(+) effector T cells, and transwell migration assays confirmed the ability of each of these chemokines to promote migration of CD8(+) effector cells in vitro. Screening by chemokine protein array identified a subset of melanoma cell lines that produced a similar broad array of chemokines. These melanoma cells more effectively recruited human CD8(+) effector T cells when implanted as xenografts in nonobese diabetic/severe combined immunodeficient mice in vivo. Chemokine blockade with specific antibodies inhibited migration of CD8(+) T cells. Our results suggest that lack of critical chemokines in a subset of melanoma metastases may limit the migration of activated T cells, which in turn could limit the effectiveness of antitumor immunity.

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Cyclic GMP-AMP containing mixed phosphodiester linkages is an endogenous high-affinity ligand for STING.

Xu Zhang, Heping Shi, Jiaxi Wu … (2013)

The presence of microbial or self DNA in the cytoplasm of mammalian cells is a danger signal detected by the DNA sensor cyclic-GMP-AMP (cGAMP) synthase (cGAS), which catalyzes the production of cGAMP that in turn serves as a second messenger to activate innate immune responses. Here we show that endogenous cGAMP in mammalian cells contains two distinct phosphodiester linkages, one between 2'-OH of GMP and 5'-phosphate of AMP, and the other between 3'-OH of AMP and 5'-phosphate of GMP. This molecule, termed 2'3'-cGAMP, is unique in that it binds to the adaptor protein STING with a much greater affinity than cGAMP molecules containing other combinations of phosphodiester linkages. The crystal structure of STING bound to 2'3'-cGAMP revealed the structural basis of this high-affinity binding and a ligand-induced conformational change in STING that may underlie its activation. Copyright © 2013 Elsevier Inc. All rights reserved.

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Author and article information

Journal

Journal ID (nlm-journal-id): 101283273

Journal ID (pubmed-jr-id): 34218

Journal ID (nlm-ta): Nat Nanotechnol

Journal ID (iso-abbrev): Nat Nanotechnol

Title: Nature nanotechnology

ISSN (Print): 1748-3387

ISSN (Electronic): 1748-3395

Publication date Nihms-submitted: 29 November 2018

Publication date (Electronic): 21 January 2019

Publication date (Print): March 2019

Publication date PMC-release: 21 July 2019

Volume: 14

Issue: 3

Pages: 269-278

Affiliations

[1 ]Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN, 37232

[2 ]Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN, 37232

[3 ]The David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA, 02139

[4 ]Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232

[5 ]Department of Biochemistry, Vanderbilt University Medical Center, Nashville, TN 37232

[6 ]Breast Cancer Research Program, Vanderbilt University Medical Center, Nashville, TN 37232

[7 ]Department of Surgery, Vanderbilt University Medical Center, Nashville, TN 37232

[8 ]Vanderbilt Ingram Cancer Center, Nashville, TN, 37232

[9 ]Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232

[10 ]Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, 37232

[11 ]Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN 37232

[12 ]Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN 37232

[13 ]Vanderbilt Institute of Nanoscale Science and Engineering, Vanderbilt University, Nashville, TN 37232

Author notes

Author Contributions

D.S. and J.T.W. conceived of and designed the experiments. D.S. performed the majority of the experiments and data analysis. K.W.B. created the ISRE responsive luciferase reporter B16.F10 cells used for longitudinal in vivo experimentation and assisted with tumour therapy studies. P.C. synthesized and characterized 2’3-cGAMP. D.S.Y and A.K.R.L obtained cryo-transmission electron micrographs of nanoparticles. S.S. synthesized and characterized the pyridyl disulfide ethyl methacrylate monomer. M.A. assisted with experimental design and cGAMP characterization. M.K. and D.B.J provided resected tumour samples from melanoma patients. J.M.B. provided guidance on and assisted with nanoString experiments and analysis of multiplexed gene expression data. D.S. and J.T.W. wrote the manuscript.

[* ] To whom correspondence should be addressed: John T. Wilson, Ph.D., 2400 Highland Avenue, 107 Olin Hall, Nashville, TN 37212, Phone: +1-615-322-6406, john.t.wilson@ 123456vanderbilt.edu

Article

Manuscript ID: NIHMS1514496

DOI: 10.1038/s41565-018-0342-5

PMC ID: 6402974

PubMed ID: 30664751

SO-VID: 69a19dfb-24fa-42af-8164-83e990bacf70

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Endosomolytic Polymersomes Increase the Activity of Cyclic Dinucleotide STING Agonists to Enhance Cancer Immunotherapy

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Most cited references 26

STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors.

Chemokine expression in melanoma metastases associated with CD8+ T-cell recruitment.

Cyclic GMP-AMP containing mixed phosphodiester linkages is an endogenous high-affinity ligand for STING.

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