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1.
Cell Rep ; 25(11): 3074-3085.e5, 2018 12 11.
Article in English | MEDLINE | ID: mdl-30540940

ABSTRACT

Intratumoral (IT) STING activation results in tumor regression in preclinical models, yet factors dictating the balance between innate and adaptive anti-tumor immunity are unclear. Here, clinical candidate STING agonist ADU-S100 (S100) is used in an IT dosing regimen optimized for adaptive immunity to uncover requirements for a T cell-driven response compatible with checkpoint inhibitors (CPIs). In contrast to high-dose tumor ablative regimens that result in systemic S100 distribution, low-dose immunogenic regimens induce local activation of tumor-specific CD8+ effector T cells that are responsible for durable anti-tumor immunity and can be enhanced with CPIs. Both hematopoietic cell STING expression and signaling through IFNAR are required for tumor-specific T cell activation, and in the context of optimized T cell responses, TNFα is dispensable for tumor control. In a poorly immunogenic model, S100 combined with CPIs generates a survival benefit and durable protection. These results provide fundamental mechanistic insights into STING-induced anti-tumor immunity.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , Immunity , Membrane Proteins/metabolism , Neoplasms/immunology , Animals , CTLA-4 Antigen/metabolism , Cell Line, Tumor , Cytokines/metabolism , Dose-Response Relationship, Immunologic , Drug Resistance, Neoplasm , Hematopoiesis , Mice, Inbred BALB C , Mice, Inbred C57BL , Neoplasms/pathology , Programmed Cell Death 1 Receptor/metabolism , S100 Proteins/administration & dosage , S100 Proteins/immunology
2.
Cell Rep ; 11(7): 1018-30, 2015 May 19.
Article in English | MEDLINE | ID: mdl-25959818

ABSTRACT

Spontaneous tumor-initiated T cell priming is dependent on IFN-ß production by tumor-resident dendritic cells. On the basis of recent observations indicating that IFN-ß expression was dependent upon activation of the host STING pathway, we hypothesized that direct engagement of STING through intratumoral (IT) administration of specific agonists would result in effective anti-tumor therapy. After proof-of-principle studies using the mouse STING agonist DMXAA showed a potent therapeutic effect, we generated synthetic cyclic dinucleotide (CDN) derivatives that activated all human STING alleles as well as murine STING. IT injection of STING agonists induced profound regression of established tumors in mice and generated substantial systemic immune responses capable of rejecting distant metastases and providing long-lived immunologic memory. Synthetic CDNs have high translational potential as a cancer therapeutic.


Subject(s)
Antineoplastic Agents/pharmacology , Membrane Proteins/antagonists & inhibitors , Neoplasms, Experimental/immunology , Nucleotides, Cyclic/pharmacology , Tumor Microenvironment/immunology , Animals , Antineoplastic Agents/chemical synthesis , Blotting, Western , Cell Line, Tumor , Enzyme-Linked Immunosorbent Assay , Gene Knockout Techniques , Humans , Macrophages , Membrane Proteins/immunology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Neoplasms, Experimental/drug therapy , Nucleotides, Cyclic/chemical synthesis , Polymerase Chain Reaction , Transfection , Xanthones/pharmacology
3.
Sci Transl Med ; 7(283): 283ra52, 2015 Apr 15.
Article in English | MEDLINE | ID: mdl-25877890

ABSTRACT

Stimulator of interferon genes (STING) is a cytosolic receptor that senses both exogenous and endogenous cytosolic cyclic dinucleotides (CDNs), activating TBK1/IRF3 (interferon regulatory factor 3), NF-κB (nuclear factor κB), and STAT6 (signal transducer and activator of transcription 6) signaling pathways to induce robust type I interferon and proinflammatory cytokine responses. CDN ligands were formulated with granulocyte-macrophage colony-stimulating factor (GM-CSF)-producing cellular cancer vaccines--termed STINGVAX--that demonstrated potent in vivo antitumor efficacy in multiple therapeutic models of established cancer. We found that rationally designed synthetic CDN derivative molecules, including one with an Rp,Rp dithio diastereomer and noncanonical c[A(2',5')pA(3',5')p] phosphate bridge structure, enhanced antitumor efficacy of STINGVAX in multiple aggressive therapeutic models of established cancer in mice. Antitumor activity was STING-dependent and correlated with increased activation of dendritic cells and tumor antigen-specific CD8(+) T cells. Tumors from STINGVAX-treated mice demonstrated marked PD-L1 (programmed death ligand 1) up-regulation, which was associated with tumor-infiltrating CD8(+)IFNγ(+) T cells. When combined with PD-1 (programmed death 1) blockade, STINGVAX induced regression of palpable, poorly immunogenic tumors that did not respond to PD-1 blockade alone.


Subject(s)
Antineoplastic Agents/chemistry , Cancer Vaccines/chemistry , Membrane Proteins/agonists , Programmed Cell Death 1 Receptor/metabolism , Animals , CD8-Positive T-Lymphocytes/cytology , Cell Line, Tumor , Cytosol/metabolism , Dendritic Cells/cytology , Female , Humans , Interferon-gamma/metabolism , Ligands , Mice , Mice, Inbred BALB C , Mice, Inbred C3H , Mice, Inbred C57BL , Monocytes/cytology , NF-kappa B/metabolism , Neoplasm Transplantation , Phosphates/chemistry , Protein Serine-Threonine Kinases/metabolism , STAT6 Transcription Factor/metabolism
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