Increased HLA-DMB Expression in the Tumor Epithelium Is Associated with Increased CTL Infiltration and Improved Prognosis in Advanced-Stage Serous Ovarian Cancer
Purpose: To evaluate the possible mechanisms influencing the infiltration of CD8 T lymphocytes into the tumor epithelium of advanced-stage serous ovarian cancers. Experimental Design: Immunohistochemical localization of CD8 T lymphocytes was done on a homogeneous population of 184 high-grade, advanc...
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| creator | CALLAHAN, Michael J NAGYMANYOKI, Zoltan BERKOWITZ, Ross S MOK, Samuel C BONOME, Tomas JOHNSON, Michael E LITKOUHI, Babak SULLIVAN, Elizabeth H HIRSCH, Michelle S MATULONIS, Ursula A LIU, Joyce BIRRER, Michael J |
| description | Purpose: To evaluate the possible mechanisms influencing the infiltration of CD8 T lymphocytes into the tumor epithelium of advanced-stage
serous ovarian cancers.
Experimental Design: Immunohistochemical localization of CD8 T lymphocytes was done on a homogeneous population of 184 high-grade, advanced-stage
serous ovarian cancer tissue specimens. Microarray analysis was done on microdissected tumor epithelium from 38 specimens
to identify genes up-regulated or down-regulated in specimens with differing numbers of tumor-infiltrating CD8 T lymphocytes.
Quantitative real-time PCR and immunohistochemistry were used to validate a candidate gene. Univariate and multivariate survival
analyses were done combining CD8 T lymphocyte number and HLA-DMB expression with standard prognostic factors.
Results: Marked CD8 T lymphocyte infiltration of the tumor epithelium is associated with a 20-month improvement in median overall
survival. Additionally, when combined with cytoreduction status and age, CD8 T lymphocyte status is an independent prognostic
factor for survival. Microarray analysis showed HLA-DMB, a component of the MHC II antigen presentation machinery, to be differentially
expressed in specimens with an abundance of tumor-infiltrating CD8 T lymphocytes. This relationship was validated at both
mRNA and protein levels. As well, high HLA-DMB expression in the tumor epithelium was associated with a significant improvement
in median overall survival in both univariate and multivariate analyses.
Conclusions: Tumor cell expression of HLA-DMB is associated with increased numbers of tumor-infiltrating CD8 T lymphocytes and both are
associated with improved survival in advanced-stage serous ovarian cancer. |
| doi_str_mv | 10.1158/1078-0432.CCR-08-0479 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_69845735</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>69845735</sourcerecordid><originalsourceid>FETCH-LOGICAL-c418t-45a696ebc5038186be359c21e175d097c76c193c92bca1e0fa212f7dafb17ef03</originalsourceid><addsrcrecordid>eNpFkc9u1DAQxiMEoqXwCCBfQOKQ4rHjOD4uYWlX2qqILmfLcSa7Rvmz2MkWHoc3rcMu7ckznt98Hs-XJG-BXgKI4hNQWaQ04-yyLL-ndI6lepacgxAy5SwXz2P8nzlLXoXwk1LIgGYvkzNQkaaKnSd_V731aALW5Hq9SL_cfCbL33uPIbihJ64n4w7JZuoGT5Z7F5PWTR1ZBbIIYbDOjLHxPt6TJ51ys45Z49rRm3FWMX1NVt3eD4dY_eaHbT8EF2bxRX0wvcU6vRvNFskd-mEK5PZgvDM9Keeaf528aEwb8M3pvEh-fF1uyut0fXu1Khfr1GZQjGkmTK5yrKygvIAir5ALZRkgSFFTJa3MLShuFausAaSNYcAaWZumAokN5RfJh6NuHPTXhGHUnQsW29b0GKfSuSoyIbmIoDiC1g8heGz03rvO-D8aqJ690fPe9bx3Hb3RdI6lin3vTg9MVYf1U9fJjAi8PwEmWNM2Pv7fhUeOAUjG6Sz08cjt3HZ37zxq-29T0TU03u40ZJpxLfNc8gcNPace</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>69845735</pqid></control><display><type>article</type><title>Increased HLA-DMB Expression in the Tumor Epithelium Is Associated with Increased CTL Infiltration and Improved Prognosis in Advanced-Stage Serous Ovarian Cancer</title><source>MEDLINE</source><source>American Association for Cancer Research</source><source>EZB-FREE-00999 freely available EZB journals</source><source>Alma/SFX Local Collection</source><creator>CALLAHAN, Michael J ; NAGYMANYOKI, Zoltan ; BERKOWITZ, Ross S ; MOK, Samuel C ; BONOME, Tomas ; JOHNSON, Michael E ; LITKOUHI, Babak ; SULLIVAN, Elizabeth H ; HIRSCH, Michelle S ; MATULONIS, Ursula A ; LIU, Joyce ; BIRRER, Michael J</creator><creatorcontrib>CALLAHAN, Michael J ; NAGYMANYOKI, Zoltan ; BERKOWITZ, Ross S ; MOK, Samuel C ; BONOME, Tomas ; JOHNSON, Michael E ; LITKOUHI, Babak ; SULLIVAN, Elizabeth H ; HIRSCH, Michelle S ; MATULONIS, Ursula A ; LIU, Joyce ; BIRRER, Michael J</creatorcontrib><description>Purpose: To evaluate the possible mechanisms influencing the infiltration of CD8 T lymphocytes into the tumor epithelium of advanced-stage
serous ovarian cancers.
Experimental Design: Immunohistochemical localization of CD8 T lymphocytes was done on a homogeneous population of 184 high-grade, advanced-stage
serous ovarian cancer tissue specimens. Microarray analysis was done on microdissected tumor epithelium from 38 specimens
to identify genes up-regulated or down-regulated in specimens with differing numbers of tumor-infiltrating CD8 T lymphocytes.
Quantitative real-time PCR and immunohistochemistry were used to validate a candidate gene. Univariate and multivariate survival
analyses were done combining CD8 T lymphocyte number and HLA-DMB expression with standard prognostic factors.
Results: Marked CD8 T lymphocyte infiltration of the tumor epithelium is associated with a 20-month improvement in median overall
survival. Additionally, when combined with cytoreduction status and age, CD8 T lymphocyte status is an independent prognostic
factor for survival. Microarray analysis showed HLA-DMB, a component of the MHC II antigen presentation machinery, to be differentially
expressed in specimens with an abundance of tumor-infiltrating CD8 T lymphocytes. This relationship was validated at both
mRNA and protein levels. As well, high HLA-DMB expression in the tumor epithelium was associated with a significant improvement
in median overall survival in both univariate and multivariate analyses.
Conclusions: Tumor cell expression of HLA-DMB is associated with increased numbers of tumor-infiltrating CD8 T lymphocytes and both are
associated with improved survival in advanced-stage serous ovarian cancer.</description><identifier>ISSN: 1078-0432</identifier><identifier>EISSN: 1557-3265</identifier><identifier>DOI: 10.1158/1078-0432.CCR-08-0479</identifier><identifier>PMID: 19047092</identifier><identifier>CODEN: CCREF4</identifier><language>eng</language><publisher>Philadelphia, PA: American Association for Cancer Research</publisher><subject>Antineoplastic agents ; Biological and medical sciences ; Cystadenocarcinoma, Serous - immunology ; Cystadenocarcinoma, Serous - metabolism ; Cystadenocarcinoma, Serous - mortality ; cytotoxic lymphocytes ; Epithelium - immunology ; Epithelium - metabolism ; Female ; Female genital diseases ; Fluorescent Antibody Technique ; Gynecology. Andrology. Obstetrics ; HLA-D Antigens - biosynthesis ; HLA-DMB ; Humans ; Immunohistochemistry ; Kaplan-Meier Estimate ; Lymphocytes, Tumor-Infiltrating - immunology ; Medical sciences ; Oligonucleotide Array Sequence Analysis ; ovarian cancer ; Ovarian Neoplasms - immunology ; Ovarian Neoplasms - metabolism ; Ovarian Neoplasms - mortality ; Pharmacology. Drug treatments ; Prognosis ; Reverse Transcriptase Polymerase Chain Reaction ; T-Lymphocytes, Cytotoxic - immunology ; Tumors</subject><ispartof>Clinical cancer research, 2008-12, Vol.14 (23), p.7667-7673</ispartof><rights>2009 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c418t-45a696ebc5038186be359c21e175d097c76c193c92bca1e0fa212f7dafb17ef03</citedby><cites>FETCH-LOGICAL-c418t-45a696ebc5038186be359c21e175d097c76c193c92bca1e0fa212f7dafb17ef03</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,3356,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=21172309$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19047092$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>CALLAHAN, Michael J</creatorcontrib><creatorcontrib>NAGYMANYOKI, Zoltan</creatorcontrib><creatorcontrib>BERKOWITZ, Ross S</creatorcontrib><creatorcontrib>MOK, Samuel C</creatorcontrib><creatorcontrib>BONOME, Tomas</creatorcontrib><creatorcontrib>JOHNSON, Michael E</creatorcontrib><creatorcontrib>LITKOUHI, Babak</creatorcontrib><creatorcontrib>SULLIVAN, Elizabeth H</creatorcontrib><creatorcontrib>HIRSCH, Michelle S</creatorcontrib><creatorcontrib>MATULONIS, Ursula A</creatorcontrib><creatorcontrib>LIU, Joyce</creatorcontrib><creatorcontrib>BIRRER, Michael J</creatorcontrib><title>Increased HLA-DMB Expression in the Tumor Epithelium Is Associated with Increased CTL Infiltration and Improved Prognosis in Advanced-Stage Serous Ovarian Cancer</title><title>Clinical cancer research</title><addtitle>Clin Cancer Res</addtitle><description>Purpose: To evaluate the possible mechanisms influencing the infiltration of CD8 T lymphocytes into the tumor epithelium of advanced-stage
serous ovarian cancers.
Experimental Design: Immunohistochemical localization of CD8 T lymphocytes was done on a homogeneous population of 184 high-grade, advanced-stage
serous ovarian cancer tissue specimens. Microarray analysis was done on microdissected tumor epithelium from 38 specimens
to identify genes up-regulated or down-regulated in specimens with differing numbers of tumor-infiltrating CD8 T lymphocytes.
Quantitative real-time PCR and immunohistochemistry were used to validate a candidate gene. Univariate and multivariate survival
analyses were done combining CD8 T lymphocyte number and HLA-DMB expression with standard prognostic factors.
Results: Marked CD8 T lymphocyte infiltration of the tumor epithelium is associated with a 20-month improvement in median overall
survival. Additionally, when combined with cytoreduction status and age, CD8 T lymphocyte status is an independent prognostic
factor for survival. Microarray analysis showed HLA-DMB, a component of the MHC II antigen presentation machinery, to be differentially
expressed in specimens with an abundance of tumor-infiltrating CD8 T lymphocytes. This relationship was validated at both
mRNA and protein levels. As well, high HLA-DMB expression in the tumor epithelium was associated with a significant improvement
in median overall survival in both univariate and multivariate analyses.
Conclusions: Tumor cell expression of HLA-DMB is associated with increased numbers of tumor-infiltrating CD8 T lymphocytes and both are
associated with improved survival in advanced-stage serous ovarian cancer.</description><subject>Antineoplastic agents</subject><subject>Biological and medical sciences</subject><subject>Cystadenocarcinoma, Serous - immunology</subject><subject>Cystadenocarcinoma, Serous - metabolism</subject><subject>Cystadenocarcinoma, Serous - mortality</subject><subject>cytotoxic lymphocytes</subject><subject>Epithelium - immunology</subject><subject>Epithelium - metabolism</subject><subject>Female</subject><subject>Female genital diseases</subject><subject>Fluorescent Antibody Technique</subject><subject>Gynecology. Andrology. Obstetrics</subject><subject>HLA-D Antigens - biosynthesis</subject><subject>HLA-DMB</subject><subject>Humans</subject><subject>Immunohistochemistry</subject><subject>Kaplan-Meier Estimate</subject><subject>Lymphocytes, Tumor-Infiltrating - immunology</subject><subject>Medical sciences</subject><subject>Oligonucleotide Array Sequence Analysis</subject><subject>ovarian cancer</subject><subject>Ovarian Neoplasms - immunology</subject><subject>Ovarian Neoplasms - metabolism</subject><subject>Ovarian Neoplasms - mortality</subject><subject>Pharmacology. Drug treatments</subject><subject>Prognosis</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>T-Lymphocytes, Cytotoxic - immunology</subject><subject>Tumors</subject><issn>1078-0432</issn><issn>1557-3265</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkc9u1DAQxiMEoqXwCCBfQOKQ4rHjOD4uYWlX2qqILmfLcSa7Rvmz2MkWHoc3rcMu7ckznt98Hs-XJG-BXgKI4hNQWaQ04-yyLL-ndI6lepacgxAy5SwXz2P8nzlLXoXwk1LIgGYvkzNQkaaKnSd_V731aALW5Hq9SL_cfCbL33uPIbihJ64n4w7JZuoGT5Z7F5PWTR1ZBbIIYbDOjLHxPt6TJ51ys45Z49rRm3FWMX1NVt3eD4dY_eaHbT8EF2bxRX0wvcU6vRvNFskd-mEK5PZgvDM9Keeaf528aEwb8M3pvEh-fF1uyut0fXu1Khfr1GZQjGkmTK5yrKygvIAir5ALZRkgSFFTJa3MLShuFausAaSNYcAaWZumAokN5RfJh6NuHPTXhGHUnQsW29b0GKfSuSoyIbmIoDiC1g8heGz03rvO-D8aqJ690fPe9bx3Hb3RdI6lin3vTg9MVYf1U9fJjAi8PwEmWNM2Pv7fhUeOAUjG6Sz08cjt3HZ37zxq-29T0TU03u40ZJpxLfNc8gcNPace</recordid><startdate>20081201</startdate><enddate>20081201</enddate><creator>CALLAHAN, Michael J</creator><creator>NAGYMANYOKI, Zoltan</creator><creator>BERKOWITZ, Ross S</creator><creator>MOK, Samuel C</creator><creator>BONOME, Tomas</creator><creator>JOHNSON, Michael E</creator><creator>LITKOUHI, Babak</creator><creator>SULLIVAN, Elizabeth H</creator><creator>HIRSCH, Michelle S</creator><creator>MATULONIS, Ursula A</creator><creator>LIU, Joyce</creator><creator>BIRRER, Michael J</creator><general>American Association for Cancer Research</general><scope>IQODW</scope><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></search><sort><creationdate>20081201</creationdate><title>Increased HLA-DMB Expression in the Tumor Epithelium Is Associated with Increased CTL Infiltration and Improved Prognosis in Advanced-Stage Serous Ovarian Cancer</title><author>CALLAHAN, Michael J ; NAGYMANYOKI, Zoltan ; BERKOWITZ, Ross S ; MOK, Samuel C ; BONOME, Tomas ; JOHNSON, Michael E ; LITKOUHI, Babak ; SULLIVAN, Elizabeth H ; HIRSCH, Michelle S ; MATULONIS, Ursula A ; LIU, Joyce ; BIRRER, Michael J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c418t-45a696ebc5038186be359c21e175d097c76c193c92bca1e0fa212f7dafb17ef03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Antineoplastic agents</topic><topic>Biological and medical sciences</topic><topic>Cystadenocarcinoma, Serous - immunology</topic><topic>Cystadenocarcinoma, Serous - metabolism</topic><topic>Cystadenocarcinoma, Serous - mortality</topic><topic>cytotoxic lymphocytes</topic><topic>Epithelium - immunology</topic><topic>Epithelium - metabolism</topic><topic>Female</topic><topic>Female genital diseases</topic><topic>Fluorescent Antibody Technique</topic><topic>Gynecology. Andrology. Obstetrics</topic><topic>HLA-D Antigens - biosynthesis</topic><topic>HLA-DMB</topic><topic>Humans</topic><topic>Immunohistochemistry</topic><topic>Kaplan-Meier Estimate</topic><topic>Lymphocytes, Tumor-Infiltrating - immunology</topic><topic>Medical sciences</topic><topic>Oligonucleotide Array Sequence Analysis</topic><topic>ovarian cancer</topic><topic>Ovarian Neoplasms - immunology</topic><topic>Ovarian Neoplasms - metabolism</topic><topic>Ovarian Neoplasms - mortality</topic><topic>Pharmacology. Drug treatments</topic><topic>Prognosis</topic><topic>Reverse Transcriptase Polymerase Chain Reaction</topic><topic>T-Lymphocytes, Cytotoxic - immunology</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>CALLAHAN, Michael J</creatorcontrib><creatorcontrib>NAGYMANYOKI, Zoltan</creatorcontrib><creatorcontrib>BERKOWITZ, Ross S</creatorcontrib><creatorcontrib>MOK, Samuel C</creatorcontrib><creatorcontrib>BONOME, Tomas</creatorcontrib><creatorcontrib>JOHNSON, Michael E</creatorcontrib><creatorcontrib>LITKOUHI, Babak</creatorcontrib><creatorcontrib>SULLIVAN, Elizabeth H</creatorcontrib><creatorcontrib>HIRSCH, Michelle S</creatorcontrib><creatorcontrib>MATULONIS, Ursula A</creatorcontrib><creatorcontrib>LIU, Joyce</creatorcontrib><creatorcontrib>BIRRER, Michael J</creatorcontrib><collection>Pascal-Francis</collection><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><jtitle>Clinical cancer research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>CALLAHAN, Michael J</au><au>NAGYMANYOKI, Zoltan</au><au>BERKOWITZ, Ross S</au><au>MOK, Samuel C</au><au>BONOME, Tomas</au><au>JOHNSON, Michael E</au><au>LITKOUHI, Babak</au><au>SULLIVAN, Elizabeth H</au><au>HIRSCH, Michelle S</au><au>MATULONIS, Ursula A</au><au>LIU, Joyce</au><au>BIRRER, Michael J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Increased HLA-DMB Expression in the Tumor Epithelium Is Associated with Increased CTL Infiltration and Improved Prognosis in Advanced-Stage Serous Ovarian Cancer</atitle><jtitle>Clinical cancer research</jtitle><addtitle>Clin Cancer Res</addtitle><date>2008-12-01</date><risdate>2008</risdate><volume>14</volume><issue>23</issue><spage>7667</spage><epage>7673</epage><pages>7667-7673</pages><issn>1078-0432</issn><eissn>1557-3265</eissn><coden>CCREF4</coden><abstract>Purpose: To evaluate the possible mechanisms influencing the infiltration of CD8 T lymphocytes into the tumor epithelium of advanced-stage
serous ovarian cancers.
Experimental Design: Immunohistochemical localization of CD8 T lymphocytes was done on a homogeneous population of 184 high-grade, advanced-stage
serous ovarian cancer tissue specimens. Microarray analysis was done on microdissected tumor epithelium from 38 specimens
to identify genes up-regulated or down-regulated in specimens with differing numbers of tumor-infiltrating CD8 T lymphocytes.
Quantitative real-time PCR and immunohistochemistry were used to validate a candidate gene. Univariate and multivariate survival
analyses were done combining CD8 T lymphocyte number and HLA-DMB expression with standard prognostic factors.
Results: Marked CD8 T lymphocyte infiltration of the tumor epithelium is associated with a 20-month improvement in median overall
survival. Additionally, when combined with cytoreduction status and age, CD8 T lymphocyte status is an independent prognostic
factor for survival. Microarray analysis showed HLA-DMB, a component of the MHC II antigen presentation machinery, to be differentially
expressed in specimens with an abundance of tumor-infiltrating CD8 T lymphocytes. This relationship was validated at both
mRNA and protein levels. As well, high HLA-DMB expression in the tumor epithelium was associated with a significant improvement
in median overall survival in both univariate and multivariate analyses.
Conclusions: Tumor cell expression of HLA-DMB is associated with increased numbers of tumor-infiltrating CD8 T lymphocytes and both are
associated with improved survival in advanced-stage serous ovarian cancer.</abstract><cop>Philadelphia, PA</cop><pub>American Association for Cancer Research</pub><pmid>19047092</pmid><doi>10.1158/1078-0432.CCR-08-0479</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Clinical cancer research, 2008-12, Vol.14 (23), p.7667-7673 |
| issn | 1078-0432 1557-3265 |
| language | eng |
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| source | MEDLINE; American Association for Cancer Research; EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
| subjects | Antineoplastic agents Biological and medical sciences Cystadenocarcinoma, Serous - immunology Cystadenocarcinoma, Serous - metabolism Cystadenocarcinoma, Serous - mortality cytotoxic lymphocytes Epithelium - immunology Epithelium - metabolism Female Female genital diseases Fluorescent Antibody Technique Gynecology. Andrology. Obstetrics HLA-D Antigens - biosynthesis HLA-DMB Humans Immunohistochemistry Kaplan-Meier Estimate Lymphocytes, Tumor-Infiltrating - immunology Medical sciences Oligonucleotide Array Sequence Analysis ovarian cancer Ovarian Neoplasms - immunology Ovarian Neoplasms - metabolism Ovarian Neoplasms - mortality Pharmacology. Drug treatments Prognosis Reverse Transcriptase Polymerase Chain Reaction T-Lymphocytes, Cytotoxic - immunology Tumors |
| title | Increased HLA-DMB Expression in the Tumor Epithelium Is Associated with Increased CTL Infiltration and Improved Prognosis in Advanced-Stage Serous Ovarian Cancer |
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