Dynamics of the Tumor Immune Microenvironment during Neoadjuvant Chemotherapy of High-Grade Serous Ovarian Cancer
The dynamic changes in the tumor immune microenvironment (TIME) triggered by neoadjuvant chemotherapy (NAC) have not been clearly defined in advanced-stage ovarian cancer. We analyzed the immunologic changes induced by NAC to correlate them with clinical outcomes. We compared the changes in the immu...
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| Veröffentlicht in: | Cancers 2022-05, Vol.14 (9), p.2308 |
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| creator | Lee, Yong Jae Woo, Ha Young Kim, Yoo-Na Park, Junsik Nam, Eun Ji Kim, Sang Wun Kim, Sunghoon Kim, Young Tae Park, Eunhyang Joung, Je-Gun Lee, Jung-Yun |
| description | The dynamic changes in the tumor immune microenvironment (TIME) triggered by neoadjuvant chemotherapy (NAC) have not been clearly defined in advanced-stage ovarian cancer. We analyzed the immunologic changes induced by NAC to correlate them with clinical outcomes. We compared the changes in the immune infiltration of high-grade serous carcinoma biopsies before and after NAC via immunohistochemistry (147 paired samples) and whole transcriptome sequencing (35 paired samples). Immunohistochemistry showed significantly increased PD-L1 levels and TIL levels after NAC. Whole transcriptome sequencing revealed that the stromal score, immune score, and cytolytic activity score significantly increased after NAC. An increased tumor-infiltrating lymphocyte (TIL) level in response to NAC was associated with shorter progression-free survival compared with decreased TIL level after NAC. In tumors with increased TIL levels after NAC, the relative fraction of CD8 T cells and regulatory T cells significantly increased with immunohistochemistry. Post-NAC tumors were enriched in gene sets associated with immune signaling pathways, such as regulatory T cell and JAK/STAT signaling pathways. NAC induced dynamic changes in the TIME that increased TIL levels, but their high abundance did not impart any survival benefit. Our data may provide therapeutic strategies to improve the survival benefit from immunotherapies in ovarian cancer. |
| doi_str_mv | 10.3390/cancers14092308 |
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We analyzed the immunologic changes induced by NAC to correlate them with clinical outcomes. We compared the changes in the immune infiltration of high-grade serous carcinoma biopsies before and after NAC via immunohistochemistry (147 paired samples) and whole transcriptome sequencing (35 paired samples). Immunohistochemistry showed significantly increased PD-L1 levels and TIL levels after NAC. Whole transcriptome sequencing revealed that the stromal score, immune score, and cytolytic activity score significantly increased after NAC. An increased tumor-infiltrating lymphocyte (TIL) level in response to NAC was associated with shorter progression-free survival compared with decreased TIL level after NAC. In tumors with increased TIL levels after NAC, the relative fraction of CD8 T cells and regulatory T cells significantly increased with immunohistochemistry. Post-NAC tumors were enriched in gene sets associated with immune signaling pathways, such as regulatory T cell and JAK/STAT signaling pathways. NAC induced dynamic changes in the TIME that increased TIL levels, but their high abundance did not impart any survival benefit. Our data may provide therapeutic strategies to improve the survival benefit from immunotherapies in ovarian cancer.</description><identifier>ISSN: 2072-6694</identifier><identifier>EISSN: 2072-6694</identifier><identifier>DOI: 10.3390/cancers14092308</identifier><identifier>PMID: 35565437</identifier><language>eng</language><publisher>Switzerland: MDPI AG</publisher><subject>Biomarkers ; Biopsy ; Cancer therapies ; CD8 antigen ; Chemotherapy ; Cytolytic activity ; Foxp3 protein ; Genetic testing ; Immunohistochemistry ; Immunoregulation ; Immunosuppression ; Immunotherapy ; Infiltration ; Lymphocytes ; Lymphocytes T ; Metastases ; Microenvironments ; Ovarian cancer ; Patients ; PD-L1 protein ; Signal transduction ; Surgery ; Transcriptomes ; Tumors</subject><ispartof>Cancers, 2022-05, Vol.14 (9), p.2308</ispartof><rights>2022 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>2022 by the authors. 2022</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c421t-87934b5253d1b097870139ac7c83a8789a16c47ce19b50c62f9fa39f99e705883</citedby><cites>FETCH-LOGICAL-c421t-87934b5253d1b097870139ac7c83a8789a16c47ce19b50c62f9fa39f99e705883</cites><orcidid>0000-0002-3078-6484 ; 0000-0003-2859-1036 ; 0000-0003-0297-3116 ; 0000-0002-7347-1052 ; 0000-0002-8342-8701 ; 0000-0001-7948-1350 ; 0000-0003-4094-2097</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9104540/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9104540/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35565437$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lee, Yong Jae</creatorcontrib><creatorcontrib>Woo, Ha Young</creatorcontrib><creatorcontrib>Kim, Yoo-Na</creatorcontrib><creatorcontrib>Park, Junsik</creatorcontrib><creatorcontrib>Nam, Eun Ji</creatorcontrib><creatorcontrib>Kim, Sang Wun</creatorcontrib><creatorcontrib>Kim, Sunghoon</creatorcontrib><creatorcontrib>Kim, Young Tae</creatorcontrib><creatorcontrib>Park, Eunhyang</creatorcontrib><creatorcontrib>Joung, Je-Gun</creatorcontrib><creatorcontrib>Lee, Jung-Yun</creatorcontrib><title>Dynamics of the Tumor Immune Microenvironment during Neoadjuvant Chemotherapy of High-Grade Serous Ovarian Cancer</title><title>Cancers</title><addtitle>Cancers (Basel)</addtitle><description>The dynamic changes in the tumor immune microenvironment (TIME) triggered by neoadjuvant chemotherapy (NAC) have not been clearly defined in advanced-stage ovarian cancer. We analyzed the immunologic changes induced by NAC to correlate them with clinical outcomes. We compared the changes in the immune infiltration of high-grade serous carcinoma biopsies before and after NAC via immunohistochemistry (147 paired samples) and whole transcriptome sequencing (35 paired samples). Immunohistochemistry showed significantly increased PD-L1 levels and TIL levels after NAC. Whole transcriptome sequencing revealed that the stromal score, immune score, and cytolytic activity score significantly increased after NAC. An increased tumor-infiltrating lymphocyte (TIL) level in response to NAC was associated with shorter progression-free survival compared with decreased TIL level after NAC. In tumors with increased TIL levels after NAC, the relative fraction of CD8 T cells and regulatory T cells significantly increased with immunohistochemistry. Post-NAC tumors were enriched in gene sets associated with immune signaling pathways, such as regulatory T cell and JAK/STAT signaling pathways. NAC induced dynamic changes in the TIME that increased TIL levels, but their high abundance did not impart any survival benefit. Our data may provide therapeutic strategies to improve the survival benefit from immunotherapies in ovarian cancer.</description><subject>Biomarkers</subject><subject>Biopsy</subject><subject>Cancer therapies</subject><subject>CD8 antigen</subject><subject>Chemotherapy</subject><subject>Cytolytic activity</subject><subject>Foxp3 protein</subject><subject>Genetic testing</subject><subject>Immunohistochemistry</subject><subject>Immunoregulation</subject><subject>Immunosuppression</subject><subject>Immunotherapy</subject><subject>Infiltration</subject><subject>Lymphocytes</subject><subject>Lymphocytes T</subject><subject>Metastases</subject><subject>Microenvironments</subject><subject>Ovarian cancer</subject><subject>Patients</subject><subject>PD-L1 protein</subject><subject>Signal transduction</subject><subject>Surgery</subject><subject>Transcriptomes</subject><subject>Tumors</subject><issn>2072-6694</issn><issn>2072-6694</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNpdUU1vUzEQtBCIVqFnbsgSFy6P-tvPFySUQlup0APlbG38_BJHsZ3aeZHy73FoqUr34tV6djSzg9B7Sj5zbsi5g-R8qVQQwzjpX6FTRjTrlDLi9bP-BJ3VuiatOKda6bfohEuppOD6FN1fHBLE4CrOI96tPL6bYi74OsYpefwjuJJ92oeSU_Rph4ephLTEP32GYT3toY3mKx9z2yywPRxJrsJy1V0WGDz-5UueKr7dQwmQ8Pyv3nfozQib6s8e3xn6_f3b3fyqu7m9vJ5_vemcYHTX9dpwsZBM8oEuiNG9JpQbcNr1HHrdG6DKCe08NQtJnGKjGYGb0Riviex7PkNfHni30yL6wTX5BTZ2W0KEcrAZgv3_J4WVXea9NZQIKUgj-PRIUPL95OvOxlCd32wg-WbLMqWENoow3aAfX0DXeSqp2TuimJH6eP0ZOn9AtaPWWvz4JIYSe0zUvki0bXx47uEJ_y8__gdZ7p5W</recordid><startdate>20220506</startdate><enddate>20220506</enddate><creator>Lee, Yong Jae</creator><creator>Woo, Ha Young</creator><creator>Kim, Yoo-Na</creator><creator>Park, Junsik</creator><creator>Nam, Eun Ji</creator><creator>Kim, Sang Wun</creator><creator>Kim, Sunghoon</creator><creator>Kim, Young Tae</creator><creator>Park, Eunhyang</creator><creator>Joung, Je-Gun</creator><creator>Lee, Jung-Yun</creator><general>MDPI AG</general><general>MDPI</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7T5</scope><scope>7TO</scope><scope>7XB</scope><scope>8FE</scope><scope>8FH</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>LK8</scope><scope>M2O</scope><scope>M7P</scope><scope>MBDVC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-3078-6484</orcidid><orcidid>https://orcid.org/0000-0003-2859-1036</orcidid><orcidid>https://orcid.org/0000-0003-0297-3116</orcidid><orcidid>https://orcid.org/0000-0002-7347-1052</orcidid><orcidid>https://orcid.org/0000-0002-8342-8701</orcidid><orcidid>https://orcid.org/0000-0001-7948-1350</orcidid><orcidid>https://orcid.org/0000-0003-4094-2097</orcidid></search><sort><creationdate>20220506</creationdate><title>Dynamics of the Tumor Immune Microenvironment during Neoadjuvant Chemotherapy of High-Grade Serous Ovarian Cancer</title><author>Lee, Yong Jae ; 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We analyzed the immunologic changes induced by NAC to correlate them with clinical outcomes. We compared the changes in the immune infiltration of high-grade serous carcinoma biopsies before and after NAC via immunohistochemistry (147 paired samples) and whole transcriptome sequencing (35 paired samples). Immunohistochemistry showed significantly increased PD-L1 levels and TIL levels after NAC. Whole transcriptome sequencing revealed that the stromal score, immune score, and cytolytic activity score significantly increased after NAC. An increased tumor-infiltrating lymphocyte (TIL) level in response to NAC was associated with shorter progression-free survival compared with decreased TIL level after NAC. In tumors with increased TIL levels after NAC, the relative fraction of CD8 T cells and regulatory T cells significantly increased with immunohistochemistry. Post-NAC tumors were enriched in gene sets associated with immune signaling pathways, such as regulatory T cell and JAK/STAT signaling pathways. NAC induced dynamic changes in the TIME that increased TIL levels, but their high abundance did not impart any survival benefit. Our data may provide therapeutic strategies to improve the survival benefit from immunotherapies in ovarian cancer.</abstract><cop>Switzerland</cop><pub>MDPI AG</pub><pmid>35565437</pmid><doi>10.3390/cancers14092308</doi><orcidid>https://orcid.org/0000-0002-3078-6484</orcidid><orcidid>https://orcid.org/0000-0003-2859-1036</orcidid><orcidid>https://orcid.org/0000-0003-0297-3116</orcidid><orcidid>https://orcid.org/0000-0002-7347-1052</orcidid><orcidid>https://orcid.org/0000-0002-8342-8701</orcidid><orcidid>https://orcid.org/0000-0001-7948-1350</orcidid><orcidid>https://orcid.org/0000-0003-4094-2097</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Biomarkers Biopsy Cancer therapies CD8 antigen Chemotherapy Cytolytic activity Foxp3 protein Genetic testing Immunohistochemistry Immunoregulation Immunosuppression Immunotherapy Infiltration Lymphocytes Lymphocytes T Metastases Microenvironments Ovarian cancer Patients PD-L1 protein Signal transduction Surgery Transcriptomes Tumors |
| title | Dynamics of the Tumor Immune Microenvironment during Neoadjuvant Chemotherapy of High-Grade Serous Ovarian Cancer |
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