Combination therapy with anti‐T‐cell immunoglobulin and mucin‐domain containing molecule 3 and radiation improves antitumor efficacy in murine hepatocellular carcinoma
Background and Aim T‐cell immunoglobulin and mucin‐domain containing molecule 3 (TIM3) has emerged as a promising immune checkpoint inhibitor target; however, immune checkpoint inhibitor monotherapy does not benefit a substantial percentage of patients. Therefore, this study investigated the antitum...
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| Veröffentlicht in: | Journal of gastroenterology and hepatology 2021-05, Vol.36 (5), p.1357-1365 |
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| container_title | Journal of gastroenterology and hepatology |
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| creator | Kim, Kyoung‐Jin Lee, Hye Won Seong, Jinsil |
| description | Background and Aim
T‐cell immunoglobulin and mucin‐domain containing molecule 3 (TIM3) has emerged as a promising immune checkpoint inhibitor target; however, immune checkpoint inhibitor monotherapy does not benefit a substantial percentage of patients. Therefore, this study investigated the antitumor effect of anti‐TIM3 therapy combined with radiation in a murine hepatocellular carcinoma (HCC) model.
Methods
The effect of radiation on TIM3 expression was determined in murine and human HCC cells using western blotting, immunohistochemistry, and flow cytometry. Tumor growth and survival rate were measured to evaluate the antitumor effect of this combination therapy. Tumor immunological parameters were assessed using flow cytometry and histology.
Results
TIM3 was upregulated in tumor‐infiltrating CD8+ and CD4+ T cells in radiation‐treated HCa‐1‐implanted mice. Combination treatment significantly delayed tumor growth compared with monotherapy (P |
| doi_str_mv | 10.1111/jgh.15319 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_journals_2522222123</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2522222123</sourcerecordid><originalsourceid>FETCH-LOGICAL-c3539-ede71aa9d4b795e6547293f0eadc512d312f14824f7e5bbf54eaad6c55b1c2f93</originalsourceid><addsrcrecordid>eNp1kU1qHDEQhUVIiCe2F7lAEGTlRdv6nXYvw5DYCQZvnHWjlkozGvQzUbdiZpcj5CK-VE4SzbSTnQuKgqqP9woeQu8puaS1rrbrzSWVnHav0IIKQRraiuVrtCDXVDZd3Z-gd-O4JYQI0sq36IRzRlsilwv0tEphcFFNLkU8bSCr3R4_ummDVZzcn1-_H2pr8B67EEpMa5-G4l2sZ4ND0S7Wu0lB1ZVOcarTxTUOyYMuHjA_glkZN1u4sMvpJ4xH-amElDFY67TSe1wlQskuAt7ATk3pYFu8ylirXI2qyRl6Y5Uf4fx5nqLvXz4_rG6bu_ubr6tPd43mkncNGGipUp0RQ9tJWErRso5bAspoSZnhlFkqrpmwLchhsFKAUmappRyoZrbjp-jjrFuf_VFgnPptKjlWy55JdijKeKUuZkrnNI4ZbL_LLqi87ynpD8H0NZj-GExlPzwrliGA-U_-S6ICVzPw6DzsX1bqv93czpJ_AQFkn3U</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2522222123</pqid></control><display><type>article</type><title>Combination therapy with anti‐T‐cell immunoglobulin and mucin‐domain containing molecule 3 and radiation improves antitumor efficacy in murine hepatocellular carcinoma</title><source>Wiley Online Library Journals Frontfile Complete</source><creator>Kim, Kyoung‐Jin ; Lee, Hye Won ; Seong, Jinsil</creator><creatorcontrib>Kim, Kyoung‐Jin ; Lee, Hye Won ; Seong, Jinsil</creatorcontrib><description>Background and Aim
T‐cell immunoglobulin and mucin‐domain containing molecule 3 (TIM3) has emerged as a promising immune checkpoint inhibitor target; however, immune checkpoint inhibitor monotherapy does not benefit a substantial percentage of patients. Therefore, this study investigated the antitumor effect of anti‐TIM3 therapy combined with radiation in a murine hepatocellular carcinoma (HCC) model.
Methods
The effect of radiation on TIM3 expression was determined in murine and human HCC cells using western blotting, immunohistochemistry, and flow cytometry. Tumor growth and survival rate were measured to evaluate the antitumor effect of this combination therapy. Tumor immunological parameters were assessed using flow cytometry and histology.
Results
TIM3 was upregulated in tumor‐infiltrating CD8+ and CD4+ T cells in radiation‐treated HCa‐1‐implanted mice. Combination treatment significantly delayed tumor growth compared with monotherapy (P < 0.01). Overall survival was improved in the combination group compared with that in the anti‐TIM3 or radiation monotherapy groups (median survival time: 52 days vs 26 or 38 days, respectively, P < 0.001). The antitumor effect of the combination treatment was associated with increased apoptosis and decreased proliferation of tumor cells and reinvigorated CD8+ T‐cell activation. CD8+ T‐cell depletion reversed the antitumor efficacy of the combination treatment. These findings suggest that CD8+ T cells play key roles in the therapeutic effect of the combination treatment.
Conclusion
Anti‐TIM3 and radiation combination therapy significantly improved the antitumor effect in a murine HCC model, as evidenced by inhibited tumor growth and increased overall survival. This approach could be a novel combined immune‐radiotherapy strategy for HCC.</description><identifier>ISSN: 0815-9319</identifier><identifier>EISSN: 1440-1746</identifier><identifier>DOI: 10.1111/jgh.15319</identifier><identifier>PMID: 33217056</identifier><language>eng</language><publisher>Australia: Wiley Subscription Services, Inc</publisher><subject>Antitumor activity ; Antitumor effect ; Apoptosis ; CD4 antigen ; CD8 antigen ; Cell activation ; Cell proliferation ; Combination therapy ; Flow cytometry ; Hepatocellular carcinoma ; Immune checkpoint inhibitor ; Immune checkpoint inhibitors ; Immunoglobulins ; Immunohistochemistry ; Liver cancer ; Lymphocytes T ; Mucin ; Radiation ; Radiation therapy ; Tumor cells ; Western blotting</subject><ispartof>Journal of gastroenterology and hepatology, 2021-05, Vol.36 (5), p.1357-1365</ispartof><rights>2020 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd</rights><rights>2020 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.</rights><rights>2021 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3539-ede71aa9d4b795e6547293f0eadc512d312f14824f7e5bbf54eaad6c55b1c2f93</citedby><cites>FETCH-LOGICAL-c3539-ede71aa9d4b795e6547293f0eadc512d312f14824f7e5bbf54eaad6c55b1c2f93</cites><orcidid>0000-0003-1794-5951 ; 0000-0002-3552-3560 ; 0000-0002-7544-0962</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fjgh.15319$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fjgh.15319$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,27901,27902,45550,45551</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33217056$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kim, Kyoung‐Jin</creatorcontrib><creatorcontrib>Lee, Hye Won</creatorcontrib><creatorcontrib>Seong, Jinsil</creatorcontrib><title>Combination therapy with anti‐T‐cell immunoglobulin and mucin‐domain containing molecule 3 and radiation improves antitumor efficacy in murine hepatocellular carcinoma</title><title>Journal of gastroenterology and hepatology</title><addtitle>J Gastroenterol Hepatol</addtitle><description>Background and Aim
T‐cell immunoglobulin and mucin‐domain containing molecule 3 (TIM3) has emerged as a promising immune checkpoint inhibitor target; however, immune checkpoint inhibitor monotherapy does not benefit a substantial percentage of patients. Therefore, this study investigated the antitumor effect of anti‐TIM3 therapy combined with radiation in a murine hepatocellular carcinoma (HCC) model.
Methods
The effect of radiation on TIM3 expression was determined in murine and human HCC cells using western blotting, immunohistochemistry, and flow cytometry. Tumor growth and survival rate were measured to evaluate the antitumor effect of this combination therapy. Tumor immunological parameters were assessed using flow cytometry and histology.
Results
TIM3 was upregulated in tumor‐infiltrating CD8+ and CD4+ T cells in radiation‐treated HCa‐1‐implanted mice. Combination treatment significantly delayed tumor growth compared with monotherapy (P < 0.01). Overall survival was improved in the combination group compared with that in the anti‐TIM3 or radiation monotherapy groups (median survival time: 52 days vs 26 or 38 days, respectively, P < 0.001). The antitumor effect of the combination treatment was associated with increased apoptosis and decreased proliferation of tumor cells and reinvigorated CD8+ T‐cell activation. CD8+ T‐cell depletion reversed the antitumor efficacy of the combination treatment. These findings suggest that CD8+ T cells play key roles in the therapeutic effect of the combination treatment.
Conclusion
Anti‐TIM3 and radiation combination therapy significantly improved the antitumor effect in a murine HCC model, as evidenced by inhibited tumor growth and increased overall survival. This approach could be a novel combined immune‐radiotherapy strategy for HCC.</description><subject>Antitumor activity</subject><subject>Antitumor effect</subject><subject>Apoptosis</subject><subject>CD4 antigen</subject><subject>CD8 antigen</subject><subject>Cell activation</subject><subject>Cell proliferation</subject><subject>Combination therapy</subject><subject>Flow cytometry</subject><subject>Hepatocellular carcinoma</subject><subject>Immune checkpoint inhibitor</subject><subject>Immune checkpoint inhibitors</subject><subject>Immunoglobulins</subject><subject>Immunohistochemistry</subject><subject>Liver cancer</subject><subject>Lymphocytes T</subject><subject>Mucin</subject><subject>Radiation</subject><subject>Radiation therapy</subject><subject>Tumor cells</subject><subject>Western blotting</subject><issn>0815-9319</issn><issn>1440-1746</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><recordid>eNp1kU1qHDEQhUVIiCe2F7lAEGTlRdv6nXYvw5DYCQZvnHWjlkozGvQzUbdiZpcj5CK-VE4SzbSTnQuKgqqP9woeQu8puaS1rrbrzSWVnHav0IIKQRraiuVrtCDXVDZd3Z-gd-O4JYQI0sq36IRzRlsilwv0tEphcFFNLkU8bSCr3R4_ummDVZzcn1-_H2pr8B67EEpMa5-G4l2sZ4ND0S7Wu0lB1ZVOcarTxTUOyYMuHjA_glkZN1u4sMvpJ4xH-amElDFY67TSe1wlQskuAt7ATk3pYFu8ylirXI2qyRl6Y5Uf4fx5nqLvXz4_rG6bu_ubr6tPd43mkncNGGipUp0RQ9tJWErRso5bAspoSZnhlFkqrpmwLchhsFKAUmappRyoZrbjp-jjrFuf_VFgnPptKjlWy55JdijKeKUuZkrnNI4ZbL_LLqi87ynpD8H0NZj-GExlPzwrliGA-U_-S6ICVzPw6DzsX1bqv93czpJ_AQFkn3U</recordid><startdate>202105</startdate><enddate>202105</enddate><creator>Kim, Kyoung‐Jin</creator><creator>Lee, Hye Won</creator><creator>Seong, Jinsil</creator><general>Wiley Subscription Services, Inc</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7T5</scope><scope>7U9</scope><scope>H94</scope><orcidid>https://orcid.org/0000-0003-1794-5951</orcidid><orcidid>https://orcid.org/0000-0002-3552-3560</orcidid><orcidid>https://orcid.org/0000-0002-7544-0962</orcidid></search><sort><creationdate>202105</creationdate><title>Combination therapy with anti‐T‐cell immunoglobulin and mucin‐domain containing molecule 3 and radiation improves antitumor efficacy in murine hepatocellular carcinoma</title><author>Kim, Kyoung‐Jin ; Lee, Hye Won ; Seong, Jinsil</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3539-ede71aa9d4b795e6547293f0eadc512d312f14824f7e5bbf54eaad6c55b1c2f93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Antitumor activity</topic><topic>Antitumor effect</topic><topic>Apoptosis</topic><topic>CD4 antigen</topic><topic>CD8 antigen</topic><topic>Cell activation</topic><topic>Cell proliferation</topic><topic>Combination therapy</topic><topic>Flow cytometry</topic><topic>Hepatocellular carcinoma</topic><topic>Immune checkpoint inhibitor</topic><topic>Immune checkpoint inhibitors</topic><topic>Immunoglobulins</topic><topic>Immunohistochemistry</topic><topic>Liver cancer</topic><topic>Lymphocytes T</topic><topic>Mucin</topic><topic>Radiation</topic><topic>Radiation therapy</topic><topic>Tumor cells</topic><topic>Western blotting</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kim, Kyoung‐Jin</creatorcontrib><creatorcontrib>Lee, Hye Won</creatorcontrib><creatorcontrib>Seong, Jinsil</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>Immunology Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><jtitle>Journal of gastroenterology and hepatology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kim, Kyoung‐Jin</au><au>Lee, Hye Won</au><au>Seong, Jinsil</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Combination therapy with anti‐T‐cell immunoglobulin and mucin‐domain containing molecule 3 and radiation improves antitumor efficacy in murine hepatocellular carcinoma</atitle><jtitle>Journal of gastroenterology and hepatology</jtitle><addtitle>J Gastroenterol Hepatol</addtitle><date>2021-05</date><risdate>2021</risdate><volume>36</volume><issue>5</issue><spage>1357</spage><epage>1365</epage><pages>1357-1365</pages><issn>0815-9319</issn><eissn>1440-1746</eissn><abstract>Background and Aim
T‐cell immunoglobulin and mucin‐domain containing molecule 3 (TIM3) has emerged as a promising immune checkpoint inhibitor target; however, immune checkpoint inhibitor monotherapy does not benefit a substantial percentage of patients. Therefore, this study investigated the antitumor effect of anti‐TIM3 therapy combined with radiation in a murine hepatocellular carcinoma (HCC) model.
Methods
The effect of radiation on TIM3 expression was determined in murine and human HCC cells using western blotting, immunohistochemistry, and flow cytometry. Tumor growth and survival rate were measured to evaluate the antitumor effect of this combination therapy. Tumor immunological parameters were assessed using flow cytometry and histology.
Results
TIM3 was upregulated in tumor‐infiltrating CD8+ and CD4+ T cells in radiation‐treated HCa‐1‐implanted mice. Combination treatment significantly delayed tumor growth compared with monotherapy (P < 0.01). Overall survival was improved in the combination group compared with that in the anti‐TIM3 or radiation monotherapy groups (median survival time: 52 days vs 26 or 38 days, respectively, P < 0.001). The antitumor effect of the combination treatment was associated with increased apoptosis and decreased proliferation of tumor cells and reinvigorated CD8+ T‐cell activation. CD8+ T‐cell depletion reversed the antitumor efficacy of the combination treatment. These findings suggest that CD8+ T cells play key roles in the therapeutic effect of the combination treatment.
Conclusion
Anti‐TIM3 and radiation combination therapy significantly improved the antitumor effect in a murine HCC model, as evidenced by inhibited tumor growth and increased overall survival. This approach could be a novel combined immune‐radiotherapy strategy for HCC.</abstract><cop>Australia</cop><pub>Wiley Subscription Services, Inc</pub><pmid>33217056</pmid><doi>10.1111/jgh.15319</doi><tpages>9</tpages><orcidid>https://orcid.org/0000-0003-1794-5951</orcidid><orcidid>https://orcid.org/0000-0002-3552-3560</orcidid><orcidid>https://orcid.org/0000-0002-7544-0962</orcidid></addata></record> |
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| subjects | Antitumor activity Antitumor effect Apoptosis CD4 antigen CD8 antigen Cell activation Cell proliferation Combination therapy Flow cytometry Hepatocellular carcinoma Immune checkpoint inhibitor Immune checkpoint inhibitors Immunoglobulins Immunohistochemistry Liver cancer Lymphocytes T Mucin Radiation Radiation therapy Tumor cells Western blotting |
| title | Combination therapy with anti‐T‐cell immunoglobulin and mucin‐domain containing molecule 3 and radiation improves antitumor efficacy in murine hepatocellular carcinoma |
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