Combination Therapy with a TLR7 Agonist and a BRD4 Inhibitor Suppresses Tumor Growth via Enhanced Immunomodulation
JQ-1 is a typical BRD4 inhibitor with the ability to directly fight tumor cells and evoke antitumor immunity via reducing the expression of PD-L1. However, problems arise with the development of JQ-1 in clinical trials, such as marked lymphoid and hematopoietic toxicity, leading to the investigation...
Gespeichert in:
| Veröffentlicht in: | International journal of molecular sciences 2024-01, Vol.25 (1), p.663 |
|---|---|
| Hauptverfasser: | , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | |
|---|---|
| container_issue | 1 |
| container_start_page | 663 |
| container_title | International journal of molecular sciences |
| container_volume | 25 |
| creator | Liu, Yong-Si Wang, Jia-Xin Jin, Guang-Yi Hu, Ming-Hao Wang, Xiao-Dong |
| description | JQ-1 is a typical BRD4 inhibitor with the ability to directly fight tumor cells and evoke antitumor immunity via reducing the expression of PD-L1. However, problems arise with the development of JQ-1 in clinical trials, such as marked lymphoid and hematopoietic toxicity, leading to the investigation of combination therapy. SZU-101 is a TLR7 agonist designed and synthesized by our group with potent immunostimulatory activity. Therefore, we hypothesized that combination therapy of SZU-101 and JQ-1 would target innate immunity and adaptive immunity simultaneously, to achieve a better antitumor efficacy than monotherapy. In this study, the repressive effects of the combination administration on tumor growth and metastasis were demonstrated in both murine breast cancer and melanoma models. In 4T1 tumor-bearing mice, i.t. treatment with SZU-101 in combination with i.p. treatment with JQ-1 suppressed the growth of tumors at both injected and uninjected sites. Combination therapy increased M1/M2 ratio in TAMs, decreased PD-L1 expression and promoted the recruitment of activated CD8
T cells in the TME. In summary, the improved therapeutic efficacy of the novel combination therapy appears to be feasible for the treatment of a diversity of cancers. |
| doi_str_mv | 10.3390/ijms25010663 |
| format | Article |
| fullrecord | <record><control><sourceid>gale_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_10779224</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A779345516</galeid><sourcerecordid>A779345516</sourcerecordid><originalsourceid>FETCH-LOGICAL-c437t-702763bebc04e0c5c1bdaaec9b3468e81a3f08504d3072124b588ddf496de2f3</originalsourceid><addsrcrecordid>eNptks1vEzEQxVcIREvhxhlZ4sKBFH_uxwmloZRIkZDK3i2vPZt1tLaDvduq_z0OLSVFyAdb4997oxm9onhL8DljDf5kdy5RgQkuS_asOCWc0gXGZfX86H1SvEpphzFlVDQvixNWU8xqJk6LuAqus15NNnjUDhDV_g7d2mlACrWb6wott8HbNCHlTS5dXH_haO0H29kpRPRj3u8jpAQJtbPLhasYbrP2xip06QflNRi0dm72wQUzj7_bvC5e9GpM8ObhPivar5ft6tti8_1qvVpuFpqzalpUmFYl66DTmAPWQpPOKAW66Rgva6iJYj2uBeaG4YoSyjtR18b0vCkN0J6dFZ_vbfdz58Bo8FNUo9xH61S8k0FZ-fTH20Fuw40kuKoaSnl2-PDgEMPPGdIknU0axlF5CHOStCGM80pwkdH3_6C7MEefxztQtKYcC_6X2qoRpPV9yI31wVQuc0_GhSBlps7_Q-VjwFkdPPQ2158IPt4LdAwpRegfhyRYHjIijzOS8XfHi3mE_4SC_QKIJLbt</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2912824054</pqid></control><display><type>article</type><title>Combination Therapy with a TLR7 Agonist and a BRD4 Inhibitor Suppresses Tumor Growth via Enhanced Immunomodulation</title><source>MDPI - Multidisciplinary Digital Publishing Institute</source><source>MEDLINE</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>PubMed Central</source><creator>Liu, Yong-Si ; Wang, Jia-Xin ; Jin, Guang-Yi ; Hu, Ming-Hao ; Wang, Xiao-Dong</creator><creatorcontrib>Liu, Yong-Si ; Wang, Jia-Xin ; Jin, Guang-Yi ; Hu, Ming-Hao ; Wang, Xiao-Dong</creatorcontrib><description>JQ-1 is a typical BRD4 inhibitor with the ability to directly fight tumor cells and evoke antitumor immunity via reducing the expression of PD-L1. However, problems arise with the development of JQ-1 in clinical trials, such as marked lymphoid and hematopoietic toxicity, leading to the investigation of combination therapy. SZU-101 is a TLR7 agonist designed and synthesized by our group with potent immunostimulatory activity. Therefore, we hypothesized that combination therapy of SZU-101 and JQ-1 would target innate immunity and adaptive immunity simultaneously, to achieve a better antitumor efficacy than monotherapy. In this study, the repressive effects of the combination administration on tumor growth and metastasis were demonstrated in both murine breast cancer and melanoma models. In 4T1 tumor-bearing mice, i.t. treatment with SZU-101 in combination with i.p. treatment with JQ-1 suppressed the growth of tumors at both injected and uninjected sites. Combination therapy increased M1/M2 ratio in TAMs, decreased PD-L1 expression and promoted the recruitment of activated CD8
T cells in the TME. In summary, the improved therapeutic efficacy of the novel combination therapy appears to be feasible for the treatment of a diversity of cancers.</description><identifier>ISSN: 1422-0067</identifier><identifier>ISSN: 1661-6596</identifier><identifier>EISSN: 1422-0067</identifier><identifier>DOI: 10.3390/ijms25010663</identifier><identifier>PMID: 38203835</identifier><language>eng</language><publisher>Switzerland: MDPI AG</publisher><subject>Adaptive immunity ; Adenine - analogs & derivatives ; Adjuvants, Immunologic ; Animals ; Apoptosis ; B cells ; B7-H1 Antigen ; Breast cancer ; Bromodomain Containing Proteins - antagonists & inhibitors ; Cancer ; Cancer therapies ; Care and treatment ; CD8-Positive T-Lymphocytes ; Cell death ; Combination therapy ; Cytokines ; Drug dosages ; Flow cytometry ; Investigations ; Ligands ; Lymphocytes ; Macrophages ; Mediation ; Melanoma ; Mice ; Nuclear Proteins ; Proteins ; Succinates ; T cells ; Toll-Like Receptor 7 - agonists ; Transcription Factors ; Tumors</subject><ispartof>International journal of molecular sciences, 2024-01, Vol.25 (1), p.663</ispartof><rights>COPYRIGHT 2024 MDPI AG</rights><rights>2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2024 by the authors. 2024</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c437t-702763bebc04e0c5c1bdaaec9b3468e81a3f08504d3072124b588ddf496de2f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10779224/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10779224/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38203835$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Liu, Yong-Si</creatorcontrib><creatorcontrib>Wang, Jia-Xin</creatorcontrib><creatorcontrib>Jin, Guang-Yi</creatorcontrib><creatorcontrib>Hu, Ming-Hao</creatorcontrib><creatorcontrib>Wang, Xiao-Dong</creatorcontrib><title>Combination Therapy with a TLR7 Agonist and a BRD4 Inhibitor Suppresses Tumor Growth via Enhanced Immunomodulation</title><title>International journal of molecular sciences</title><addtitle>Int J Mol Sci</addtitle><description>JQ-1 is a typical BRD4 inhibitor with the ability to directly fight tumor cells and evoke antitumor immunity via reducing the expression of PD-L1. However, problems arise with the development of JQ-1 in clinical trials, such as marked lymphoid and hematopoietic toxicity, leading to the investigation of combination therapy. SZU-101 is a TLR7 agonist designed and synthesized by our group with potent immunostimulatory activity. Therefore, we hypothesized that combination therapy of SZU-101 and JQ-1 would target innate immunity and adaptive immunity simultaneously, to achieve a better antitumor efficacy than monotherapy. In this study, the repressive effects of the combination administration on tumor growth and metastasis were demonstrated in both murine breast cancer and melanoma models. In 4T1 tumor-bearing mice, i.t. treatment with SZU-101 in combination with i.p. treatment with JQ-1 suppressed the growth of tumors at both injected and uninjected sites. Combination therapy increased M1/M2 ratio in TAMs, decreased PD-L1 expression and promoted the recruitment of activated CD8
T cells in the TME. In summary, the improved therapeutic efficacy of the novel combination therapy appears to be feasible for the treatment of a diversity of cancers.</description><subject>Adaptive immunity</subject><subject>Adenine - analogs & derivatives</subject><subject>Adjuvants, Immunologic</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>B cells</subject><subject>B7-H1 Antigen</subject><subject>Breast cancer</subject><subject>Bromodomain Containing Proteins - antagonists & inhibitors</subject><subject>Cancer</subject><subject>Cancer therapies</subject><subject>Care and treatment</subject><subject>CD8-Positive T-Lymphocytes</subject><subject>Cell death</subject><subject>Combination therapy</subject><subject>Cytokines</subject><subject>Drug dosages</subject><subject>Flow cytometry</subject><subject>Investigations</subject><subject>Ligands</subject><subject>Lymphocytes</subject><subject>Macrophages</subject><subject>Mediation</subject><subject>Melanoma</subject><subject>Mice</subject><subject>Nuclear Proteins</subject><subject>Proteins</subject><subject>Succinates</subject><subject>T cells</subject><subject>Toll-Like Receptor 7 - agonists</subject><subject>Transcription Factors</subject><subject>Tumors</subject><issn>1422-0067</issn><issn>1661-6596</issn><issn>1422-0067</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNptks1vEzEQxVcIREvhxhlZ4sKBFH_uxwmloZRIkZDK3i2vPZt1tLaDvduq_z0OLSVFyAdb4997oxm9onhL8DljDf5kdy5RgQkuS_asOCWc0gXGZfX86H1SvEpphzFlVDQvixNWU8xqJk6LuAqus15NNnjUDhDV_g7d2mlACrWb6wott8HbNCHlTS5dXH_haO0H29kpRPRj3u8jpAQJtbPLhasYbrP2xip06QflNRi0dm72wQUzj7_bvC5e9GpM8ObhPivar5ft6tti8_1qvVpuFpqzalpUmFYl66DTmAPWQpPOKAW66Rgva6iJYj2uBeaG4YoSyjtR18b0vCkN0J6dFZ_vbfdz58Bo8FNUo9xH61S8k0FZ-fTH20Fuw40kuKoaSnl2-PDgEMPPGdIknU0axlF5CHOStCGM80pwkdH3_6C7MEefxztQtKYcC_6X2qoRpPV9yI31wVQuc0_GhSBlps7_Q-VjwFkdPPQ2158IPt4LdAwpRegfhyRYHjIijzOS8XfHi3mE_4SC_QKIJLbt</recordid><startdate>20240101</startdate><enddate>20240101</enddate><creator>Liu, Yong-Si</creator><creator>Wang, Jia-Xin</creator><creator>Jin, Guang-Yi</creator><creator>Hu, Ming-Hao</creator><creator>Wang, Xiao-Dong</creator><general>MDPI AG</general><general>MDPI</general><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>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>MBDVC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20240101</creationdate><title>Combination Therapy with a TLR7 Agonist and a BRD4 Inhibitor Suppresses Tumor Growth via Enhanced Immunomodulation</title><author>Liu, Yong-Si ; Wang, Jia-Xin ; Jin, Guang-Yi ; Hu, Ming-Hao ; Wang, Xiao-Dong</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c437t-702763bebc04e0c5c1bdaaec9b3468e81a3f08504d3072124b588ddf496de2f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Adaptive immunity</topic><topic>Adenine - analogs & derivatives</topic><topic>Adjuvants, Immunologic</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>B cells</topic><topic>B7-H1 Antigen</topic><topic>Breast cancer</topic><topic>Bromodomain Containing Proteins - antagonists & inhibitors</topic><topic>Cancer</topic><topic>Cancer therapies</topic><topic>Care and treatment</topic><topic>CD8-Positive T-Lymphocytes</topic><topic>Cell death</topic><topic>Combination therapy</topic><topic>Cytokines</topic><topic>Drug dosages</topic><topic>Flow cytometry</topic><topic>Investigations</topic><topic>Ligands</topic><topic>Lymphocytes</topic><topic>Macrophages</topic><topic>Mediation</topic><topic>Melanoma</topic><topic>Mice</topic><topic>Nuclear Proteins</topic><topic>Proteins</topic><topic>Succinates</topic><topic>T cells</topic><topic>Toll-Like Receptor 7 - agonists</topic><topic>Transcription Factors</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Liu, Yong-Si</creatorcontrib><creatorcontrib>Wang, Jia-Xin</creatorcontrib><creatorcontrib>Jin, Guang-Yi</creatorcontrib><creatorcontrib>Hu, Ming-Hao</creatorcontrib><creatorcontrib>Wang, Xiao-Dong</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Research Library</collection><collection>Research Library (Corporate)</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>International journal of molecular sciences</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Liu, Yong-Si</au><au>Wang, Jia-Xin</au><au>Jin, Guang-Yi</au><au>Hu, Ming-Hao</au><au>Wang, Xiao-Dong</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Combination Therapy with a TLR7 Agonist and a BRD4 Inhibitor Suppresses Tumor Growth via Enhanced Immunomodulation</atitle><jtitle>International journal of molecular sciences</jtitle><addtitle>Int J Mol Sci</addtitle><date>2024-01-01</date><risdate>2024</risdate><volume>25</volume><issue>1</issue><spage>663</spage><pages>663-</pages><issn>1422-0067</issn><issn>1661-6596</issn><eissn>1422-0067</eissn><abstract>JQ-1 is a typical BRD4 inhibitor with the ability to directly fight tumor cells and evoke antitumor immunity via reducing the expression of PD-L1. However, problems arise with the development of JQ-1 in clinical trials, such as marked lymphoid and hematopoietic toxicity, leading to the investigation of combination therapy. SZU-101 is a TLR7 agonist designed and synthesized by our group with potent immunostimulatory activity. Therefore, we hypothesized that combination therapy of SZU-101 and JQ-1 would target innate immunity and adaptive immunity simultaneously, to achieve a better antitumor efficacy than monotherapy. In this study, the repressive effects of the combination administration on tumor growth and metastasis were demonstrated in both murine breast cancer and melanoma models. In 4T1 tumor-bearing mice, i.t. treatment with SZU-101 in combination with i.p. treatment with JQ-1 suppressed the growth of tumors at both injected and uninjected sites. Combination therapy increased M1/M2 ratio in TAMs, decreased PD-L1 expression and promoted the recruitment of activated CD8
T cells in the TME. In summary, the improved therapeutic efficacy of the novel combination therapy appears to be feasible for the treatment of a diversity of cancers.</abstract><cop>Switzerland</cop><pub>MDPI AG</pub><pmid>38203835</pmid><doi>10.3390/ijms25010663</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1422-0067 |
| ispartof | International journal of molecular sciences, 2024-01, Vol.25 (1), p.663 |
| issn | 1422-0067 1661-6596 1422-0067 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_10779224 |
| source | MDPI - Multidisciplinary Digital Publishing Institute; MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central |
| subjects | Adaptive immunity Adenine - analogs & derivatives Adjuvants, Immunologic Animals Apoptosis B cells B7-H1 Antigen Breast cancer Bromodomain Containing Proteins - antagonists & inhibitors Cancer Cancer therapies Care and treatment CD8-Positive T-Lymphocytes Cell death Combination therapy Cytokines Drug dosages Flow cytometry Investigations Ligands Lymphocytes Macrophages Mediation Melanoma Mice Nuclear Proteins Proteins Succinates T cells Toll-Like Receptor 7 - agonists Transcription Factors Tumors |
| title | Combination Therapy with a TLR7 Agonist and a BRD4 Inhibitor Suppresses Tumor Growth via Enhanced Immunomodulation |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-09T20%3A44%3A09IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Combination%20Therapy%20with%20a%20TLR7%20Agonist%20and%20a%20BRD4%20Inhibitor%20Suppresses%20Tumor%20Growth%20via%20Enhanced%20Immunomodulation&rft.jtitle=International%20journal%20of%20molecular%20sciences&rft.au=Liu,%20Yong-Si&rft.date=2024-01-01&rft.volume=25&rft.issue=1&rft.spage=663&rft.pages=663-&rft.issn=1422-0067&rft.eissn=1422-0067&rft_id=info:doi/10.3390/ijms25010663&rft_dat=%3Cgale_pubme%3EA779345516%3C/gale_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2912824054&rft_id=info:pmid/38203835&rft_galeid=A779345516&rfr_iscdi=true |