Tumor cellular proliferation is associated with enhanced immune checkpoint expression in stage I non–small cell lung cancer
Ki67 is a marker for tumor proliferative activity and is known to have prognostic significance in multiple solid malignancies. We sought to characterize the relationships among Ki67 expression, immune cell infiltration, and immune checkpoint expression in patients with resected non–small cell lung c...
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| Veröffentlicht in: | The Journal of thoracic and cardiovascular surgery 2019-09, Vol.158 (3), p.911-919.e6 |
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| creator | Mitchell, Kyle G. Parra, Edwin R. Nelson, David B. Zhang, Jiexin Wistuba, Ignacio I. Fujimoto, Junya Roth, Jack A. Antonoff, Mara B. Corsini, Erin M. Vaporciyan, Ara A. Hofstetter, Wayne L. Mehran, Reza J. Swisher, Stephen G. Rice, David C. Sepesi, Boris Walsh, Garrett L. Behrens, Carmen Kalhor, Neda Weissferdt, Annikka Moran, Cesar A. Lee, J. Jack |
| description | Ki67 is a marker for tumor proliferative activity and is known to have prognostic significance in multiple solid malignancies. We sought to characterize the relationships among Ki67 expression, immune cell infiltration, and immune checkpoint expression in patients with resected non–small cell lung cancer.
Specimens of patients undergoing resection of stage I to III non–small cell lung cancer (1997-2012) were analyzed using tissue microarrays. Proliferative index was quantified as the percentage of malignant cells expressing Ki67. Checkpoints expressed on malignant cells (programmed death ligand 1, B7H3, B7H4, indoleamine 2,3-dioxygenase 1) and lymphocytes (T-cell immunoglobulin and mucin-domain containing 3, V-domain suppressor of T-cell activation, tumor necrosis factor receptor superfamily member 4, lymphocyte activation gene 3, inducible T-cell co-stimulator) were analyzed in intratumoral and stromal compartments, respectively. Immune cell densities were quantified in intratumoral and peritumoral compartments in a representative subset.
A total of 190 patients met inclusion criteria. Higher Ki67 expression was noted in squamous cell carcinoma (median 31.4% positive malignant cells vs 15.2% adenocarcinoma, P |
| doi_str_mv | 10.1016/j.jtcvs.2019.04.084 |
| format | Article |
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Specimens of patients undergoing resection of stage I to III non–small cell lung cancer (1997-2012) were analyzed using tissue microarrays. Proliferative index was quantified as the percentage of malignant cells expressing Ki67. Checkpoints expressed on malignant cells (programmed death ligand 1, B7H3, B7H4, indoleamine 2,3-dioxygenase 1) and lymphocytes (T-cell immunoglobulin and mucin-domain containing 3, V-domain suppressor of T-cell activation, tumor necrosis factor receptor superfamily member 4, lymphocyte activation gene 3, inducible T-cell co-stimulator) were analyzed in intratumoral and stromal compartments, respectively. Immune cell densities were quantified in intratumoral and peritumoral compartments in a representative subset.
A total of 190 patients met inclusion criteria. Higher Ki67 expression was noted in squamous cell carcinoma (median 31.4% positive malignant cells vs 15.2% adenocarcinoma, P < .001), advanced-stage tumors (25.7% stages II/III vs 20.8% stage I, P = .013), and poorly differentiated tumors (28.8% vs 15.4% well/moderately, P < .001). Ki67 was positively correlated with intratumoral expression of programmed death ligand 1, B7-H3, and indoleamine 2,3-dioxygenase 1, and elevated stromal expression of lymphocyte activation gene 3 and inducible T-cell co-stimulator. Ki67 expression was inversely associated with intratumoral densities of CD57+ and CD4+ cells. The relationship between Ki67 and checkpoint expression was strongest in stage I tumors. Among patients with stage I, increased Ki67 was independently associated with worse overall survival.
Increased Ki67 expression is associated with biologically aggressive non–small cell lung cancer, enhanced immune checkpoint expression, and reduced intratumoral immune cell infiltration. These findings were strongest in early-stage disease and warrant further investigation in the context of novel therapeutic agents.</description><identifier>ISSN: 0022-5223</identifier><identifier>EISSN: 1097-685X</identifier><identifier>DOI: 10.1016/j.jtcvs.2019.04.084</identifier><identifier>PMID: 31235357</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Aged ; Antigens, CD - analysis ; B7 Antigens - analysis ; B7-H1 Antigen - analysis ; Biomarkers, Tumor - analysis ; Carcinoma, Non-Small-Cell Lung - chemistry ; Carcinoma, Non-Small-Cell Lung - immunology ; Carcinoma, Non-Small-Cell Lung - pathology ; Carcinoma, Non-Small-Cell Lung - surgery ; Cell Differentiation ; Cell Proliferation ; Female ; Humans ; immune checkpoints ; immune microenvironment ; Indoleamine-Pyrrole 2,3,-Dioxygenase - analysis ; Inducible T-Cell Co-Stimulator Protein - analysis ; Ki-67 Antigen - analysis ; Ki67 ; Lung Neoplasms - chemistry ; Lung Neoplasms - immunology ; Lung Neoplasms - pathology ; Lung Neoplasms - surgery ; Lymphocyte Activation Gene 3 Protein ; Male ; Middle Aged ; Neoplasm Staging ; non–small cell lung cancer ; Retrospective Studies ; Tumor Microenvironment ; V-Set Domain-Containing T-Cell Activation Inhibitor 1 - analysis</subject><ispartof>The Journal of thoracic and cardiovascular surgery, 2019-09, Vol.158 (3), p.911-919.e6</ispartof><rights>2019 The American Association for Thoracic Surgery</rights><rights>Copyright © 2019 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c459t-85f4b9afd4fc43024d815b7f8ab952d381fbe05600e1514ffd07ba555a6b43303</citedby><cites>FETCH-LOGICAL-c459t-85f4b9afd4fc43024d815b7f8ab952d381fbe05600e1514ffd07ba555a6b43303</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.jtcvs.2019.04.084$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,780,784,885,3549,27923,27924,45994</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31235357$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mitchell, Kyle G.</creatorcontrib><creatorcontrib>Parra, Edwin R.</creatorcontrib><creatorcontrib>Nelson, David B.</creatorcontrib><creatorcontrib>Zhang, Jiexin</creatorcontrib><creatorcontrib>Wistuba, Ignacio I.</creatorcontrib><creatorcontrib>Fujimoto, Junya</creatorcontrib><creatorcontrib>Roth, Jack A.</creatorcontrib><creatorcontrib>Antonoff, Mara B.</creatorcontrib><creatorcontrib>Corsini, Erin M.</creatorcontrib><creatorcontrib>Vaporciyan, Ara A.</creatorcontrib><creatorcontrib>Hofstetter, Wayne L.</creatorcontrib><creatorcontrib>Mehran, Reza J.</creatorcontrib><creatorcontrib>Swisher, Stephen G.</creatorcontrib><creatorcontrib>Rice, David C.</creatorcontrib><creatorcontrib>Sepesi, Boris</creatorcontrib><creatorcontrib>Walsh, Garrett L.</creatorcontrib><creatorcontrib>Behrens, Carmen</creatorcontrib><creatorcontrib>Kalhor, Neda</creatorcontrib><creatorcontrib>Weissferdt, Annikka</creatorcontrib><creatorcontrib>Moran, Cesar A.</creatorcontrib><creatorcontrib>Lee, J. Jack</creatorcontrib><creatorcontrib>MD Anderson Lung Cancer Immune Microenvironment Working Group</creatorcontrib><title>Tumor cellular proliferation is associated with enhanced immune checkpoint expression in stage I non–small cell lung cancer</title><title>The Journal of thoracic and cardiovascular surgery</title><addtitle>J Thorac Cardiovasc Surg</addtitle><description>Ki67 is a marker for tumor proliferative activity and is known to have prognostic significance in multiple solid malignancies. We sought to characterize the relationships among Ki67 expression, immune cell infiltration, and immune checkpoint expression in patients with resected non–small cell lung cancer.
Specimens of patients undergoing resection of stage I to III non–small cell lung cancer (1997-2012) were analyzed using tissue microarrays. Proliferative index was quantified as the percentage of malignant cells expressing Ki67. Checkpoints expressed on malignant cells (programmed death ligand 1, B7H3, B7H4, indoleamine 2,3-dioxygenase 1) and lymphocytes (T-cell immunoglobulin and mucin-domain containing 3, V-domain suppressor of T-cell activation, tumor necrosis factor receptor superfamily member 4, lymphocyte activation gene 3, inducible T-cell co-stimulator) were analyzed in intratumoral and stromal compartments, respectively. Immune cell densities were quantified in intratumoral and peritumoral compartments in a representative subset.
A total of 190 patients met inclusion criteria. Higher Ki67 expression was noted in squamous cell carcinoma (median 31.4% positive malignant cells vs 15.2% adenocarcinoma, P < .001), advanced-stage tumors (25.7% stages II/III vs 20.8% stage I, P = .013), and poorly differentiated tumors (28.8% vs 15.4% well/moderately, P < .001). Ki67 was positively correlated with intratumoral expression of programmed death ligand 1, B7-H3, and indoleamine 2,3-dioxygenase 1, and elevated stromal expression of lymphocyte activation gene 3 and inducible T-cell co-stimulator. Ki67 expression was inversely associated with intratumoral densities of CD57+ and CD4+ cells. The relationship between Ki67 and checkpoint expression was strongest in stage I tumors. Among patients with stage I, increased Ki67 was independently associated with worse overall survival.
Increased Ki67 expression is associated with biologically aggressive non–small cell lung cancer, enhanced immune checkpoint expression, and reduced intratumoral immune cell infiltration. These findings were strongest in early-stage disease and warrant further investigation in the context of novel therapeutic agents.</description><subject>Aged</subject><subject>Antigens, CD - analysis</subject><subject>B7 Antigens - analysis</subject><subject>B7-H1 Antigen - analysis</subject><subject>Biomarkers, Tumor - analysis</subject><subject>Carcinoma, Non-Small-Cell Lung - chemistry</subject><subject>Carcinoma, Non-Small-Cell Lung - immunology</subject><subject>Carcinoma, Non-Small-Cell Lung - pathology</subject><subject>Carcinoma, Non-Small-Cell Lung - surgery</subject><subject>Cell Differentiation</subject><subject>Cell Proliferation</subject><subject>Female</subject><subject>Humans</subject><subject>immune checkpoints</subject><subject>immune microenvironment</subject><subject>Indoleamine-Pyrrole 2,3,-Dioxygenase - analysis</subject><subject>Inducible T-Cell Co-Stimulator Protein - analysis</subject><subject>Ki-67 Antigen - analysis</subject><subject>Ki67</subject><subject>Lung Neoplasms - chemistry</subject><subject>Lung Neoplasms - immunology</subject><subject>Lung Neoplasms - pathology</subject><subject>Lung Neoplasms - surgery</subject><subject>Lymphocyte Activation Gene 3 Protein</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Neoplasm Staging</subject><subject>non–small cell lung cancer</subject><subject>Retrospective Studies</subject><subject>Tumor Microenvironment</subject><subject>V-Set Domain-Containing T-Cell Activation Inhibitor 1 - analysis</subject><issn>0022-5223</issn><issn>1097-685X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kctu1DAUhiMEokPhCZCQl2wSjm-5LEBCFZdKldgUiZ3lOMczHhI72MkUFki8A2_Ik5DMlAo2rKwj_xf7fFn2lEJBgZYv9sV-ModUMKBNAaKAWtzLNhSaKi9r-el-tgFgLJeM8bPsUUp7AKgW7cPsjFPGJZfVJvt-PQ8hEoN9P_c6kjGG3lmMenLBE5eITikYpyfsyI2bdgT9TnuzTG4YZo_E7NB8HoPzE8GvY8SUjkZP0qS3SC6JD_7Xj59p0H1_rCH97LfErCHxcfbA6j7hk9vzPPv49s31xfv86sO7y4vXV7kRspnyWlrRNtp2whrBgYmuprKtbK3bRrKO19S2CLIEQCqpsLaDqtVSSl22gnPg59mrU-44twN2Bv0Uda_G6AYdv6mgnfr3xrud2oaDqqHijFVLwPPbgBi-zJgmNbi0_kZ7DHNSjImygRLKepHyk9TEkFJEe1dDQa3g1F4dwakVnAKhFnCL69nfL7zz_CG1CF6eBLjs6eAwqmQcriRcRDOpLrj_FvwG6Eav_g</recordid><startdate>20190901</startdate><enddate>20190901</enddate><creator>Mitchell, Kyle G.</creator><creator>Parra, Edwin R.</creator><creator>Nelson, David B.</creator><creator>Zhang, Jiexin</creator><creator>Wistuba, Ignacio I.</creator><creator>Fujimoto, Junya</creator><creator>Roth, Jack A.</creator><creator>Antonoff, Mara B.</creator><creator>Corsini, Erin M.</creator><creator>Vaporciyan, Ara A.</creator><creator>Hofstetter, Wayne L.</creator><creator>Mehran, Reza J.</creator><creator>Swisher, Stephen G.</creator><creator>Rice, David C.</creator><creator>Sepesi, Boris</creator><creator>Walsh, Garrett L.</creator><creator>Behrens, Carmen</creator><creator>Kalhor, Neda</creator><creator>Weissferdt, Annikka</creator><creator>Moran, Cesar A.</creator><creator>Lee, J. Jack</creator><general>Elsevier Inc</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>7X8</scope><scope>5PM</scope></search><sort><creationdate>20190901</creationdate><title>Tumor cellular proliferation is associated with enhanced immune checkpoint expression in stage I non–small cell lung cancer</title><author>Mitchell, Kyle G. ; Parra, Edwin R. ; Nelson, David B. ; Zhang, Jiexin ; Wistuba, Ignacio I. ; Fujimoto, Junya ; Roth, Jack A. ; Antonoff, Mara B. ; Corsini, Erin M. ; Vaporciyan, Ara A. ; Hofstetter, Wayne L. ; Mehran, Reza J. ; Swisher, Stephen G. ; Rice, David C. ; Sepesi, Boris ; Walsh, Garrett L. ; Behrens, Carmen ; Kalhor, Neda ; Weissferdt, Annikka ; Moran, Cesar A. ; Lee, J. Jack</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c459t-85f4b9afd4fc43024d815b7f8ab952d381fbe05600e1514ffd07ba555a6b43303</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Aged</topic><topic>Antigens, CD - analysis</topic><topic>B7 Antigens - analysis</topic><topic>B7-H1 Antigen - analysis</topic><topic>Biomarkers, Tumor - analysis</topic><topic>Carcinoma, Non-Small-Cell Lung - chemistry</topic><topic>Carcinoma, Non-Small-Cell Lung - immunology</topic><topic>Carcinoma, Non-Small-Cell Lung - pathology</topic><topic>Carcinoma, Non-Small-Cell Lung - surgery</topic><topic>Cell Differentiation</topic><topic>Cell Proliferation</topic><topic>Female</topic><topic>Humans</topic><topic>immune checkpoints</topic><topic>immune microenvironment</topic><topic>Indoleamine-Pyrrole 2,3,-Dioxygenase - analysis</topic><topic>Inducible T-Cell Co-Stimulator Protein - analysis</topic><topic>Ki-67 Antigen - analysis</topic><topic>Ki67</topic><topic>Lung Neoplasms - chemistry</topic><topic>Lung Neoplasms - immunology</topic><topic>Lung Neoplasms - pathology</topic><topic>Lung Neoplasms - surgery</topic><topic>Lymphocyte Activation Gene 3 Protein</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Neoplasm Staging</topic><topic>non–small cell lung cancer</topic><topic>Retrospective Studies</topic><topic>Tumor Microenvironment</topic><topic>V-Set Domain-Containing T-Cell Activation Inhibitor 1 - analysis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mitchell, Kyle G.</creatorcontrib><creatorcontrib>Parra, Edwin R.</creatorcontrib><creatorcontrib>Nelson, David B.</creatorcontrib><creatorcontrib>Zhang, Jiexin</creatorcontrib><creatorcontrib>Wistuba, Ignacio I.</creatorcontrib><creatorcontrib>Fujimoto, Junya</creatorcontrib><creatorcontrib>Roth, Jack A.</creatorcontrib><creatorcontrib>Antonoff, Mara B.</creatorcontrib><creatorcontrib>Corsini, Erin M.</creatorcontrib><creatorcontrib>Vaporciyan, Ara A.</creatorcontrib><creatorcontrib>Hofstetter, Wayne L.</creatorcontrib><creatorcontrib>Mehran, Reza J.</creatorcontrib><creatorcontrib>Swisher, Stephen G.</creatorcontrib><creatorcontrib>Rice, David C.</creatorcontrib><creatorcontrib>Sepesi, Boris</creatorcontrib><creatorcontrib>Walsh, Garrett L.</creatorcontrib><creatorcontrib>Behrens, Carmen</creatorcontrib><creatorcontrib>Kalhor, Neda</creatorcontrib><creatorcontrib>Weissferdt, Annikka</creatorcontrib><creatorcontrib>Moran, Cesar A.</creatorcontrib><creatorcontrib>Lee, J. Jack</creatorcontrib><creatorcontrib>MD Anderson Lung Cancer Immune Microenvironment Working Group</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>The Journal of thoracic and cardiovascular surgery</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mitchell, Kyle G.</au><au>Parra, Edwin R.</au><au>Nelson, David B.</au><au>Zhang, Jiexin</au><au>Wistuba, Ignacio I.</au><au>Fujimoto, Junya</au><au>Roth, Jack A.</au><au>Antonoff, Mara B.</au><au>Corsini, Erin M.</au><au>Vaporciyan, Ara A.</au><au>Hofstetter, Wayne L.</au><au>Mehran, Reza J.</au><au>Swisher, Stephen G.</au><au>Rice, David C.</au><au>Sepesi, Boris</au><au>Walsh, Garrett L.</au><au>Behrens, Carmen</au><au>Kalhor, Neda</au><au>Weissferdt, Annikka</au><au>Moran, Cesar A.</au><au>Lee, J. Jack</au><aucorp>MD Anderson Lung Cancer Immune Microenvironment Working Group</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Tumor cellular proliferation is associated with enhanced immune checkpoint expression in stage I non–small cell lung cancer</atitle><jtitle>The Journal of thoracic and cardiovascular surgery</jtitle><addtitle>J Thorac Cardiovasc Surg</addtitle><date>2019-09-01</date><risdate>2019</risdate><volume>158</volume><issue>3</issue><spage>911</spage><epage>919.e6</epage><pages>911-919.e6</pages><issn>0022-5223</issn><eissn>1097-685X</eissn><abstract>Ki67 is a marker for tumor proliferative activity and is known to have prognostic significance in multiple solid malignancies. We sought to characterize the relationships among Ki67 expression, immune cell infiltration, and immune checkpoint expression in patients with resected non–small cell lung cancer.
Specimens of patients undergoing resection of stage I to III non–small cell lung cancer (1997-2012) were analyzed using tissue microarrays. Proliferative index was quantified as the percentage of malignant cells expressing Ki67. Checkpoints expressed on malignant cells (programmed death ligand 1, B7H3, B7H4, indoleamine 2,3-dioxygenase 1) and lymphocytes (T-cell immunoglobulin and mucin-domain containing 3, V-domain suppressor of T-cell activation, tumor necrosis factor receptor superfamily member 4, lymphocyte activation gene 3, inducible T-cell co-stimulator) were analyzed in intratumoral and stromal compartments, respectively. Immune cell densities were quantified in intratumoral and peritumoral compartments in a representative subset.
A total of 190 patients met inclusion criteria. Higher Ki67 expression was noted in squamous cell carcinoma (median 31.4% positive malignant cells vs 15.2% adenocarcinoma, P < .001), advanced-stage tumors (25.7% stages II/III vs 20.8% stage I, P = .013), and poorly differentiated tumors (28.8% vs 15.4% well/moderately, P < .001). Ki67 was positively correlated with intratumoral expression of programmed death ligand 1, B7-H3, and indoleamine 2,3-dioxygenase 1, and elevated stromal expression of lymphocyte activation gene 3 and inducible T-cell co-stimulator. Ki67 expression was inversely associated with intratumoral densities of CD57+ and CD4+ cells. The relationship between Ki67 and checkpoint expression was strongest in stage I tumors. Among patients with stage I, increased Ki67 was independently associated with worse overall survival.
Increased Ki67 expression is associated with biologically aggressive non–small cell lung cancer, enhanced immune checkpoint expression, and reduced intratumoral immune cell infiltration. These findings were strongest in early-stage disease and warrant further investigation in the context of novel therapeutic agents.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>31235357</pmid><doi>10.1016/j.jtcvs.2019.04.084</doi><oa>free_for_read</oa></addata></record> |
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| ispartof | The Journal of thoracic and cardiovascular surgery, 2019-09, Vol.158 (3), p.911-919.e6 |
| issn | 0022-5223 1097-685X |
| language | eng |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; ScienceDirect Journals (5 years ago - present) |
| subjects | Aged Antigens, CD - analysis B7 Antigens - analysis B7-H1 Antigen - analysis Biomarkers, Tumor - analysis Carcinoma, Non-Small-Cell Lung - chemistry Carcinoma, Non-Small-Cell Lung - immunology Carcinoma, Non-Small-Cell Lung - pathology Carcinoma, Non-Small-Cell Lung - surgery Cell Differentiation Cell Proliferation Female Humans immune checkpoints immune microenvironment Indoleamine-Pyrrole 2,3,-Dioxygenase - analysis Inducible T-Cell Co-Stimulator Protein - analysis Ki-67 Antigen - analysis Ki67 Lung Neoplasms - chemistry Lung Neoplasms - immunology Lung Neoplasms - pathology Lung Neoplasms - surgery Lymphocyte Activation Gene 3 Protein Male Middle Aged Neoplasm Staging non–small cell lung cancer Retrospective Studies Tumor Microenvironment V-Set Domain-Containing T-Cell Activation Inhibitor 1 - analysis |
| title | Tumor cellular proliferation is associated with enhanced immune checkpoint expression in stage I non–small cell lung cancer |
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