TNFα and Radioresistant Stromal Cells Are Essential for Therapeutic Efficacy of Cyclic Dinucleotide STING Agonists in Nonimmunogenic Tumors
The cGAS-STING cytosolic DNA sensing pathway may play an integral role in the initiation of antitumor immune responses. Studies evaluating the immunogenicity of various cyclic dinucleotide (CDN) STING agonists administered by intratumoral (i.t.) injection showed potent induction of inflammation, tum...
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| Veröffentlicht in: | Cancer immunology research 2018-04, Vol.6 (4), p.422-433 |
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| creator | Francica, Brian J Ghasemzadeh, Ali Desbien, Anthony L Theodros, Debebe Sivick, Kelsey E Reiner, Gabrielle L Hix Glickman, Laura Marciscano, Ariel E Sharabi, Andrew B Leong, Meredith L McWhirter, Sarah M Dubensky, Jr, Thomas W Pardoll, Drew M Drake, Charles G |
| description | The cGAS-STING cytosolic DNA sensing pathway may play an integral role in the initiation of antitumor immune responses. Studies evaluating the immunogenicity of various cyclic dinucleotide (CDN) STING agonists administered by intratumoral (i.t.) injection showed potent induction of inflammation, tumor necrosis, and, in some cases, durable tumor-specific adaptive immunity. However, the specific immune mechanisms underlying these responses remain incompletely defined. The majority of these studies have focused on the effect of CDNs on immune cells but have not conclusively interrogated the role of stromal cells in the acute rejection of the CDN-injected tumor. Here, we revealed a mechanism of STING agonist-mediated tumor response that relied on both stromal and immune cells to achieve tumor regression and clearance. Using knockout and bone marrow chimeric mice, we showed that although bone marrow-derived TNFα was necessary for CDN-induced necrosis, STING signaling in radioresistant stromal cells was also essential for CDN-mediated tumor rejection. These results provide evidence for crosstalk between stromal and hematopoietic cells during CDN-mediated tumor collapse after i.t. administration. These mechanistic insights may prove critical in the clinical development of STING agonists.
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| doi_str_mv | 10.1158/2326-6066.CIR-17-0263 |
| format | Article |
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.</description><subject>Animals</subject><subject>Antigen-Presenting Cells - immunology</subject><subject>Antigen-Presenting Cells - metabolism</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Bone Marrow - metabolism</subject><subject>Cell Line, Tumor</subject><subject>Cytokines - metabolism</subject><subject>Disease Models, Animal</subject><subject>Female</subject><subject>Humans</subject><subject>Immunity, Innate</subject><subject>Interferon-beta - metabolism</subject><subject>Melanoma, Experimental</subject><subject>Membrane Proteins - agonists</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Necrosis - metabolism</subject><subject>Necrosis - pathology</subject><subject>Neoplasms - drug therapy</subject><subject>Neoplasms - etiology</subject><subject>Neoplasms - metabolism</subject><subject>Neoplasms - pathology</subject><subject>Nucleotides, Cyclic - pharmacology</subject><subject>Radiation Tolerance - drug effects</subject><subject>Radiation Tolerance - genetics</subject><subject>Signal Transduction - drug effects</subject><subject>Stromal Cells - metabolism</subject><subject>Stromal Cells - pathology</subject><subject>Stromal Cells - radiation effects</subject><subject>Tumor Burden - drug effects</subject><subject>Tumor Microenvironment - immunology</subject><subject>Tumor Necrosis Factor-alpha - metabolism</subject><issn>2326-6066</issn><issn>2326-6074</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkctu1DAUhiMEolXpI4C8ZJPiay4bpFGYlpGqQWrD2nLs46lRYg92gjTvwMvwIjwTHnUYgTc--s9_fl--onhL8A0hovlAGa3KClfVTbd5KEldYlqxF8XlSa_5y3NdVRfFdUrfcF5Nw4ngr4sL2vKa0ppcFj_77e3vX0h5gx6UcSFCcmlWfkaPcwyTGlEH45jQKgJapwR-dlmzIaL-CaLawzI7jdbWOq30AQWLuoMes_TJ-UWPEGZnAD32m-0dWu2Cz-EJOY-2uZymxYcd-OzulynE9KZ4ZdWY4Pq0XxVfb9d997m8_3K36Vb3pWYtm0tDQddAucCgrGCMcEyGVnBh7dAQziqjYAA1sNZowZkBII1hiuncwI1p2VXx8Tl3vwwTGJ1fFdUo99FNKh5kUE7-3_HuSe7CD1lRIgSnOeD9KSCG7wukWU4u6fxRykNYkqQY121DWYuzVTxbdQwpRbDnYwiWR5jyCEoeQckMU5JaHmHmuXf_3vE89Rcd-wPYL58V</recordid><startdate>20180401</startdate><enddate>20180401</enddate><creator>Francica, Brian J</creator><creator>Ghasemzadeh, Ali</creator><creator>Desbien, Anthony L</creator><creator>Theodros, Debebe</creator><creator>Sivick, Kelsey E</creator><creator>Reiner, Gabrielle L</creator><creator>Hix Glickman, Laura</creator><creator>Marciscano, Ariel E</creator><creator>Sharabi, Andrew B</creator><creator>Leong, Meredith L</creator><creator>McWhirter, Sarah M</creator><creator>Dubensky, Jr, Thomas W</creator><creator>Pardoll, Drew M</creator><creator>Drake, Charles G</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20180401</creationdate><title>TNFα and Radioresistant Stromal Cells Are Essential for Therapeutic Efficacy of Cyclic Dinucleotide STING Agonists in Nonimmunogenic Tumors</title><author>Francica, Brian J ; Ghasemzadeh, Ali ; Desbien, Anthony L ; Theodros, Debebe ; Sivick, Kelsey E ; Reiner, Gabrielle L ; Hix Glickman, Laura ; Marciscano, Ariel E ; Sharabi, Andrew B ; Leong, Meredith L ; McWhirter, Sarah M ; Dubensky, Jr, Thomas W ; Pardoll, Drew M ; Drake, Charles G</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c393t-d2ec7e2450eaf5331401b9545ffb81436daebeab39dc543dee18d3a3c6da08d93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Animals</topic><topic>Antigen-Presenting Cells - immunology</topic><topic>Antigen-Presenting Cells - metabolism</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Bone Marrow - metabolism</topic><topic>Cell Line, Tumor</topic><topic>Cytokines - metabolism</topic><topic>Disease Models, Animal</topic><topic>Female</topic><topic>Humans</topic><topic>Immunity, Innate</topic><topic>Interferon-beta - metabolism</topic><topic>Melanoma, Experimental</topic><topic>Membrane Proteins - agonists</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Necrosis - metabolism</topic><topic>Necrosis - pathology</topic><topic>Neoplasms - drug therapy</topic><topic>Neoplasms - etiology</topic><topic>Neoplasms - metabolism</topic><topic>Neoplasms - pathology</topic><topic>Nucleotides, Cyclic - pharmacology</topic><topic>Radiation Tolerance - drug effects</topic><topic>Radiation Tolerance - genetics</topic><topic>Signal Transduction - drug effects</topic><topic>Stromal Cells - metabolism</topic><topic>Stromal Cells - pathology</topic><topic>Stromal Cells - radiation effects</topic><topic>Tumor Burden - drug effects</topic><topic>Tumor Microenvironment - immunology</topic><topic>Tumor Necrosis Factor-alpha - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Francica, Brian J</creatorcontrib><creatorcontrib>Ghasemzadeh, Ali</creatorcontrib><creatorcontrib>Desbien, Anthony L</creatorcontrib><creatorcontrib>Theodros, Debebe</creatorcontrib><creatorcontrib>Sivick, Kelsey E</creatorcontrib><creatorcontrib>Reiner, Gabrielle L</creatorcontrib><creatorcontrib>Hix Glickman, Laura</creatorcontrib><creatorcontrib>Marciscano, Ariel E</creatorcontrib><creatorcontrib>Sharabi, Andrew B</creatorcontrib><creatorcontrib>Leong, Meredith L</creatorcontrib><creatorcontrib>McWhirter, Sarah M</creatorcontrib><creatorcontrib>Dubensky, Jr, Thomas W</creatorcontrib><creatorcontrib>Pardoll, Drew M</creatorcontrib><creatorcontrib>Drake, Charles G</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cancer immunology research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Francica, Brian J</au><au>Ghasemzadeh, Ali</au><au>Desbien, Anthony L</au><au>Theodros, Debebe</au><au>Sivick, Kelsey E</au><au>Reiner, Gabrielle L</au><au>Hix Glickman, Laura</au><au>Marciscano, Ariel E</au><au>Sharabi, Andrew B</au><au>Leong, Meredith L</au><au>McWhirter, Sarah M</au><au>Dubensky, Jr, Thomas W</au><au>Pardoll, Drew M</au><au>Drake, Charles G</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>TNFα and Radioresistant Stromal Cells Are Essential for Therapeutic Efficacy of Cyclic Dinucleotide STING Agonists in Nonimmunogenic Tumors</atitle><jtitle>Cancer immunology research</jtitle><addtitle>Cancer Immunol Res</addtitle><date>2018-04-01</date><risdate>2018</risdate><volume>6</volume><issue>4</issue><spage>422</spage><epage>433</epage><pages>422-433</pages><issn>2326-6066</issn><eissn>2326-6074</eissn><abstract>The cGAS-STING cytosolic DNA sensing pathway may play an integral role in the initiation of antitumor immune responses. Studies evaluating the immunogenicity of various cyclic dinucleotide (CDN) STING agonists administered by intratumoral (i.t.) injection showed potent induction of inflammation, tumor necrosis, and, in some cases, durable tumor-specific adaptive immunity. However, the specific immune mechanisms underlying these responses remain incompletely defined. The majority of these studies have focused on the effect of CDNs on immune cells but have not conclusively interrogated the role of stromal cells in the acute rejection of the CDN-injected tumor. Here, we revealed a mechanism of STING agonist-mediated tumor response that relied on both stromal and immune cells to achieve tumor regression and clearance. Using knockout and bone marrow chimeric mice, we showed that although bone marrow-derived TNFα was necessary for CDN-induced necrosis, STING signaling in radioresistant stromal cells was also essential for CDN-mediated tumor rejection. These results provide evidence for crosstalk between stromal and hematopoietic cells during CDN-mediated tumor collapse after i.t. administration. These mechanistic insights may prove critical in the clinical development of STING agonists.
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| ispartof | Cancer immunology research, 2018-04, Vol.6 (4), p.422-433 |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; American Association for Cancer Research |
| subjects | Animals Antigen-Presenting Cells - immunology Antigen-Presenting Cells - metabolism Antineoplastic Agents - pharmacology Bone Marrow - metabolism Cell Line, Tumor Cytokines - metabolism Disease Models, Animal Female Humans Immunity, Innate Interferon-beta - metabolism Melanoma, Experimental Membrane Proteins - agonists Mice Mice, Knockout Necrosis - metabolism Necrosis - pathology Neoplasms - drug therapy Neoplasms - etiology Neoplasms - metabolism Neoplasms - pathology Nucleotides, Cyclic - pharmacology Radiation Tolerance - drug effects Radiation Tolerance - genetics Signal Transduction - drug effects Stromal Cells - metabolism Stromal Cells - pathology Stromal Cells - radiation effects Tumor Burden - drug effects Tumor Microenvironment - immunology Tumor Necrosis Factor-alpha - metabolism |
| title | TNFα and Radioresistant Stromal Cells Are Essential for Therapeutic Efficacy of Cyclic Dinucleotide STING Agonists in Nonimmunogenic Tumors |
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