Mathematical Modeling of the Metastatic Colorectal Cancer Microenvironment Defines the Importance of Cytotoxic Lymphocyte Infiltration and Presence of PD-L1 on Antigen Presenting Cells
Background Although immune-based therapy has proven efficacious for some patients with microsatellite instability (MSI) colon cancers, a majority of patients receive limited benefit. Conversely, select patients with microsatellite stable (MSS) tumors respond to checkpoint blockade, necessitating nov...
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| Veröffentlicht in: | Annals of surgical oncology 2019-09, Vol.26 (9), p.2821-2830 |
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| creator | Lazarus, Jenny Oneka, Morgan D. Barua, Souptik Maj, Tomasz Lanfranca, Mirna Perusina Delrosario, Lawrence Sun, Lei Smith, J. Joshua D’Angelica, Michael I. Shia, Jinru Fang, Jiayun M. Shi, Jiaqi Di Magliano, Marina Pasca Zou, Weiping Rao, Arvind Frankel, Timothy L. |
| description | Background
Although immune-based therapy has proven efficacious for some patients with microsatellite instability (MSI) colon cancers, a majority of patients receive limited benefit. Conversely, select patients with microsatellite stable (MSS) tumors respond to checkpoint blockade, necessitating novel ways to study the immune tumor microenvironment (TME). We used phenotypic and spatial data from infiltrating immune and tumor cells to model cellular mixing to predict disease specific outcomes in patients with colorectal liver metastases.
Methods
Formalin fixed paraffin embedded metastatic colon cancer tissue from 195 patients were subjected to multiplex immunohistochemistry (mfIHC). After phenotyping, the G-function was calculated for each patient and cell type. Data was correlated with clinical outcomes and survival.
Results
High tumor cell to cytotoxic T lymphocyte (TC-CTL) mixing was associated with both a pro-inflammatory and immunosuppressive TME characterized by increased CTL infiltration and PD-L1
+
expression, respectively. Presence and engagement of antigen presenting cells (APC) and helper T cells (Th) were associated with greater TC-CTL mixing and improved 5-year disease specific survival compared to patients with a low degree of mixing (42% vs. 16%,
p
= 0.0275). Comparison of measured mixing to a calculated theoretical random mixing revealed that PD-L1 expression on APCs resulted in an environment where CTLs were non-randomly less associated with TCs, highlighting their biologic significance.
Conclusion
Evaluation of immune interactions within the TME of metastatic colon cancer using mfIHC in combination with mathematical modeling characterized cellular mixing of TCs and CTLs, providing a novel strategy to better predict clinical outcomes while identifying potential candidates for immune based therapies. |
| doi_str_mv | 10.1245/s10434-019-07508-3 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6684475</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>931405111</sourcerecordid><originalsourceid>FETCH-LOGICAL-c473t-be7a3172e340370311453e59bc6093035331974fb71567a51ae5778e1c62f7213</originalsourceid><addsrcrecordid>eNp9UctuEzEUHSEQLYUfYIEs9gO2rx8zG6RqyqNSIrqAteVM7iSuZuxgO1XzZ3weniYU2LCydc_jHt1TVa8Zfce4kO8TowJETVlbUy1pU8OT6pzJMhKqYU_Ln6qmbrmSZ9WLlG4pZRqofF6dAeOSglDn1c-lzVucbHa9HckyrHF0fkPCQMqYLDHblGeQdGEMEftcWJ31PUaydH0M6O9cDH5Cn8kVDs5jelBeT7sQ80ycvbpDDjncF5vFYdptQ3_IheIHN-ZY3IMn1q_JTcSEJ8XNVb1gpACXPrsN-hOY53AdjmN6WT0b7Jjw1em9qL5_-vit-1Ivvn6-7i4XdS805HqF2gLTHEFQ0BQYExJQtqte0RYoSADWajGsNJNKW8ksSq0bZL3ig-YMLqoPR9_dfjXhui8Zoh3NLrrJxoMJ1pl_Ee-2ZhPujFKNEFoWg7cngxh-7DFlcxv20ZfMhnMNUlFoC4kfSeWkKUUcHhcwauayzbFsU8o2D2UbKKI3f0d7lPxutxDgSEgF8huMf1b_x_YX9xu4Hw</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>227356039</pqid></control><display><type>article</type><title>Mathematical Modeling of the Metastatic Colorectal Cancer Microenvironment Defines the Importance of Cytotoxic Lymphocyte Infiltration and Presence of PD-L1 on Antigen Presenting Cells</title><source>MEDLINE</source><source>SpringerLink Journals - AutoHoldings</source><creator>Lazarus, Jenny ; Oneka, Morgan D. ; Barua, Souptik ; Maj, Tomasz ; Lanfranca, Mirna Perusina ; Delrosario, Lawrence ; Sun, Lei ; Smith, J. Joshua ; D’Angelica, Michael I. ; Shia, Jinru ; Fang, Jiayun M. ; Shi, Jiaqi ; Di Magliano, Marina Pasca ; Zou, Weiping ; Rao, Arvind ; Frankel, Timothy L.</creator><creatorcontrib>Lazarus, Jenny ; Oneka, Morgan D. ; Barua, Souptik ; Maj, Tomasz ; Lanfranca, Mirna Perusina ; Delrosario, Lawrence ; Sun, Lei ; Smith, J. Joshua ; D’Angelica, Michael I. ; Shia, Jinru ; Fang, Jiayun M. ; Shi, Jiaqi ; Di Magliano, Marina Pasca ; Zou, Weiping ; Rao, Arvind ; Frankel, Timothy L.</creatorcontrib><description>Background
Although immune-based therapy has proven efficacious for some patients with microsatellite instability (MSI) colon cancers, a majority of patients receive limited benefit. Conversely, select patients with microsatellite stable (MSS) tumors respond to checkpoint blockade, necessitating novel ways to study the immune tumor microenvironment (TME). We used phenotypic and spatial data from infiltrating immune and tumor cells to model cellular mixing to predict disease specific outcomes in patients with colorectal liver metastases.
Methods
Formalin fixed paraffin embedded metastatic colon cancer tissue from 195 patients were subjected to multiplex immunohistochemistry (mfIHC). After phenotyping, the G-function was calculated for each patient and cell type. Data was correlated with clinical outcomes and survival.
Results
High tumor cell to cytotoxic T lymphocyte (TC-CTL) mixing was associated with both a pro-inflammatory and immunosuppressive TME characterized by increased CTL infiltration and PD-L1
+
expression, respectively. Presence and engagement of antigen presenting cells (APC) and helper T cells (Th) were associated with greater TC-CTL mixing and improved 5-year disease specific survival compared to patients with a low degree of mixing (42% vs. 16%,
p
= 0.0275). Comparison of measured mixing to a calculated theoretical random mixing revealed that PD-L1 expression on APCs resulted in an environment where CTLs were non-randomly less associated with TCs, highlighting their biologic significance.
Conclusion
Evaluation of immune interactions within the TME of metastatic colon cancer using mfIHC in combination with mathematical modeling characterized cellular mixing of TCs and CTLs, providing a novel strategy to better predict clinical outcomes while identifying potential candidates for immune based therapies.</description><identifier>ISSN: 1068-9265</identifier><identifier>EISSN: 1534-4681</identifier><identifier>DOI: 10.1245/s10434-019-07508-3</identifier><identifier>PMID: 31250346</identifier><language>eng</language><publisher>Cham: Springer International Publishing</publisher><subject>Adenomatous polyposis coli ; Antigen-presenting cells ; Antigen-Presenting Cells - immunology ; Antigens ; B7-H1 Antigen - immunology ; B7-H1 Antigen - metabolism ; Biomarkers, Tumor - immunology ; Biomarkers, Tumor - metabolism ; Cell survival ; Clinical outcomes ; Colon cancer ; Colorectal cancer ; Colorectal carcinoma ; Colorectal Neoplasms - immunology ; Colorectal Neoplasms - metabolism ; Colorectal Neoplasms - pathology ; Cytotoxicity ; Female ; Follow-Up Studies ; Humans ; Immune checkpoint ; Immunohistochemistry ; Inflammation ; Liver Neoplasms - immunology ; Liver Neoplasms - metabolism ; Liver Neoplasms - secondary ; Lymphocytes T ; Lymphocytes, Tumor-Infiltrating - immunology ; Male ; Mathematical models ; Medicine ; Medicine & Public Health ; Metastases ; Metastasis ; Microsatellite instability ; Middle Aged ; Models, Theoretical ; Oncology ; Paraffin ; PD-L1 protein ; Phenotyping ; Prognosis ; Surgery ; Surgical Oncology ; Survival Rate ; T-Lymphocytes, Cytotoxic - immunology ; Translational Research and Biomarkers ; Tumor cells ; Tumor Microenvironment - immunology ; Tumors</subject><ispartof>Annals of surgical oncology, 2019-09, Vol.26 (9), p.2821-2830</ispartof><rights>Society of Surgical Oncology 2019</rights><rights>Annals of Surgical Oncology is a copyright of Springer, (2019). All Rights Reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c473t-be7a3172e340370311453e59bc6093035331974fb71567a51ae5778e1c62f7213</citedby><cites>FETCH-LOGICAL-c473t-be7a3172e340370311453e59bc6093035331974fb71567a51ae5778e1c62f7213</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1245/s10434-019-07508-3$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1245/s10434-019-07508-3$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>230,314,780,784,885,27924,27925,41488,42557,51319</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31250346$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lazarus, Jenny</creatorcontrib><creatorcontrib>Oneka, Morgan D.</creatorcontrib><creatorcontrib>Barua, Souptik</creatorcontrib><creatorcontrib>Maj, Tomasz</creatorcontrib><creatorcontrib>Lanfranca, Mirna Perusina</creatorcontrib><creatorcontrib>Delrosario, Lawrence</creatorcontrib><creatorcontrib>Sun, Lei</creatorcontrib><creatorcontrib>Smith, J. Joshua</creatorcontrib><creatorcontrib>D’Angelica, Michael I.</creatorcontrib><creatorcontrib>Shia, Jinru</creatorcontrib><creatorcontrib>Fang, Jiayun M.</creatorcontrib><creatorcontrib>Shi, Jiaqi</creatorcontrib><creatorcontrib>Di Magliano, Marina Pasca</creatorcontrib><creatorcontrib>Zou, Weiping</creatorcontrib><creatorcontrib>Rao, Arvind</creatorcontrib><creatorcontrib>Frankel, Timothy L.</creatorcontrib><title>Mathematical Modeling of the Metastatic Colorectal Cancer Microenvironment Defines the Importance of Cytotoxic Lymphocyte Infiltration and Presence of PD-L1 on Antigen Presenting Cells</title><title>Annals of surgical oncology</title><addtitle>Ann Surg Oncol</addtitle><addtitle>Ann Surg Oncol</addtitle><description>Background
Although immune-based therapy has proven efficacious for some patients with microsatellite instability (MSI) colon cancers, a majority of patients receive limited benefit. Conversely, select patients with microsatellite stable (MSS) tumors respond to checkpoint blockade, necessitating novel ways to study the immune tumor microenvironment (TME). We used phenotypic and spatial data from infiltrating immune and tumor cells to model cellular mixing to predict disease specific outcomes in patients with colorectal liver metastases.
Methods
Formalin fixed paraffin embedded metastatic colon cancer tissue from 195 patients were subjected to multiplex immunohistochemistry (mfIHC). After phenotyping, the G-function was calculated for each patient and cell type. Data was correlated with clinical outcomes and survival.
Results
High tumor cell to cytotoxic T lymphocyte (TC-CTL) mixing was associated with both a pro-inflammatory and immunosuppressive TME characterized by increased CTL infiltration and PD-L1
+
expression, respectively. Presence and engagement of antigen presenting cells (APC) and helper T cells (Th) were associated with greater TC-CTL mixing and improved 5-year disease specific survival compared to patients with a low degree of mixing (42% vs. 16%,
p
= 0.0275). Comparison of measured mixing to a calculated theoretical random mixing revealed that PD-L1 expression on APCs resulted in an environment where CTLs were non-randomly less associated with TCs, highlighting their biologic significance.
Conclusion
Evaluation of immune interactions within the TME of metastatic colon cancer using mfIHC in combination with mathematical modeling characterized cellular mixing of TCs and CTLs, providing a novel strategy to better predict clinical outcomes while identifying potential candidates for immune based therapies.</description><subject>Adenomatous polyposis coli</subject><subject>Antigen-presenting cells</subject><subject>Antigen-Presenting Cells - immunology</subject><subject>Antigens</subject><subject>B7-H1 Antigen - immunology</subject><subject>B7-H1 Antigen - metabolism</subject><subject>Biomarkers, Tumor - immunology</subject><subject>Biomarkers, Tumor - metabolism</subject><subject>Cell survival</subject><subject>Clinical outcomes</subject><subject>Colon cancer</subject><subject>Colorectal cancer</subject><subject>Colorectal carcinoma</subject><subject>Colorectal Neoplasms - immunology</subject><subject>Colorectal Neoplasms - metabolism</subject><subject>Colorectal Neoplasms - pathology</subject><subject>Cytotoxicity</subject><subject>Female</subject><subject>Follow-Up Studies</subject><subject>Humans</subject><subject>Immune checkpoint</subject><subject>Immunohistochemistry</subject><subject>Inflammation</subject><subject>Liver Neoplasms - immunology</subject><subject>Liver Neoplasms - metabolism</subject><subject>Liver Neoplasms - secondary</subject><subject>Lymphocytes T</subject><subject>Lymphocytes, Tumor-Infiltrating - immunology</subject><subject>Male</subject><subject>Mathematical models</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Metastases</subject><subject>Metastasis</subject><subject>Microsatellite instability</subject><subject>Middle Aged</subject><subject>Models, Theoretical</subject><subject>Oncology</subject><subject>Paraffin</subject><subject>PD-L1 protein</subject><subject>Phenotyping</subject><subject>Prognosis</subject><subject>Surgery</subject><subject>Surgical Oncology</subject><subject>Survival Rate</subject><subject>T-Lymphocytes, Cytotoxic - immunology</subject><subject>Translational Research and Biomarkers</subject><subject>Tumor cells</subject><subject>Tumor Microenvironment - immunology</subject><subject>Tumors</subject><issn>1068-9265</issn><issn>1534-4681</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><recordid>eNp9UctuEzEUHSEQLYUfYIEs9gO2rx8zG6RqyqNSIrqAteVM7iSuZuxgO1XzZ3weniYU2LCydc_jHt1TVa8Zfce4kO8TowJETVlbUy1pU8OT6pzJMhKqYU_Ln6qmbrmSZ9WLlG4pZRqofF6dAeOSglDn1c-lzVucbHa9HckyrHF0fkPCQMqYLDHblGeQdGEMEftcWJ31PUaydH0M6O9cDH5Cn8kVDs5jelBeT7sQ80ycvbpDDjncF5vFYdptQ3_IheIHN-ZY3IMn1q_JTcSEJ8XNVb1gpACXPrsN-hOY53AdjmN6WT0b7Jjw1em9qL5_-vit-1Ivvn6-7i4XdS805HqF2gLTHEFQ0BQYExJQtqte0RYoSADWajGsNJNKW8ksSq0bZL3ig-YMLqoPR9_dfjXhui8Zoh3NLrrJxoMJ1pl_Ee-2ZhPujFKNEFoWg7cngxh-7DFlcxv20ZfMhnMNUlFoC4kfSeWkKUUcHhcwauayzbFsU8o2D2UbKKI3f0d7lPxutxDgSEgF8huMf1b_x_YX9xu4Hw</recordid><startdate>20190901</startdate><enddate>20190901</enddate><creator>Lazarus, Jenny</creator><creator>Oneka, Morgan D.</creator><creator>Barua, Souptik</creator><creator>Maj, Tomasz</creator><creator>Lanfranca, Mirna Perusina</creator><creator>Delrosario, Lawrence</creator><creator>Sun, Lei</creator><creator>Smith, J. Joshua</creator><creator>D’Angelica, Michael I.</creator><creator>Shia, Jinru</creator><creator>Fang, Jiayun M.</creator><creator>Shi, Jiaqi</creator><creator>Di Magliano, Marina Pasca</creator><creator>Zou, Weiping</creator><creator>Rao, Arvind</creator><creator>Frankel, Timothy L.</creator><general>Springer International Publishing</general><general>Springer Nature B.V</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>7TO</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>H94</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>5PM</scope></search><sort><creationdate>20190901</creationdate><title>Mathematical Modeling of the Metastatic Colorectal Cancer Microenvironment Defines the Importance of Cytotoxic Lymphocyte Infiltration and Presence of PD-L1 on Antigen Presenting Cells</title><author>Lazarus, Jenny ; Oneka, Morgan D. ; Barua, Souptik ; Maj, Tomasz ; Lanfranca, Mirna Perusina ; Delrosario, Lawrence ; Sun, Lei ; Smith, J. Joshua ; D’Angelica, Michael I. ; Shia, Jinru ; Fang, Jiayun M. ; Shi, Jiaqi ; Di Magliano, Marina Pasca ; Zou, Weiping ; Rao, Arvind ; Frankel, Timothy L.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c473t-be7a3172e340370311453e59bc6093035331974fb71567a51ae5778e1c62f7213</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Adenomatous polyposis coli</topic><topic>Antigen-presenting cells</topic><topic>Antigen-Presenting Cells - immunology</topic><topic>Antigens</topic><topic>B7-H1 Antigen - immunology</topic><topic>B7-H1 Antigen - metabolism</topic><topic>Biomarkers, Tumor - immunology</topic><topic>Biomarkers, Tumor - metabolism</topic><topic>Cell survival</topic><topic>Clinical outcomes</topic><topic>Colon cancer</topic><topic>Colorectal cancer</topic><topic>Colorectal carcinoma</topic><topic>Colorectal Neoplasms - immunology</topic><topic>Colorectal Neoplasms - metabolism</topic><topic>Colorectal Neoplasms - pathology</topic><topic>Cytotoxicity</topic><topic>Female</topic><topic>Follow-Up Studies</topic><topic>Humans</topic><topic>Immune checkpoint</topic><topic>Immunohistochemistry</topic><topic>Inflammation</topic><topic>Liver Neoplasms - immunology</topic><topic>Liver Neoplasms - metabolism</topic><topic>Liver Neoplasms - secondary</topic><topic>Lymphocytes T</topic><topic>Lymphocytes, Tumor-Infiltrating - immunology</topic><topic>Male</topic><topic>Mathematical models</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Metastases</topic><topic>Metastasis</topic><topic>Microsatellite instability</topic><topic>Middle Aged</topic><topic>Models, Theoretical</topic><topic>Oncology</topic><topic>Paraffin</topic><topic>PD-L1 protein</topic><topic>Phenotyping</topic><topic>Prognosis</topic><topic>Surgery</topic><topic>Surgical Oncology</topic><topic>Survival Rate</topic><topic>T-Lymphocytes, Cytotoxic - immunology</topic><topic>Translational Research and Biomarkers</topic><topic>Tumor cells</topic><topic>Tumor Microenvironment - immunology</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lazarus, Jenny</creatorcontrib><creatorcontrib>Oneka, Morgan D.</creatorcontrib><creatorcontrib>Barua, Souptik</creatorcontrib><creatorcontrib>Maj, Tomasz</creatorcontrib><creatorcontrib>Lanfranca, Mirna Perusina</creatorcontrib><creatorcontrib>Delrosario, Lawrence</creatorcontrib><creatorcontrib>Sun, Lei</creatorcontrib><creatorcontrib>Smith, J. Joshua</creatorcontrib><creatorcontrib>D’Angelica, Michael I.</creatorcontrib><creatorcontrib>Shia, Jinru</creatorcontrib><creatorcontrib>Fang, Jiayun M.</creatorcontrib><creatorcontrib>Shi, Jiaqi</creatorcontrib><creatorcontrib>Di Magliano, Marina Pasca</creatorcontrib><creatorcontrib>Zou, Weiping</creatorcontrib><creatorcontrib>Rao, Arvind</creatorcontrib><creatorcontrib>Frankel, Timothy L.</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>Oncogenes and Growth Factors Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical 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 China</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Annals of surgical oncology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lazarus, Jenny</au><au>Oneka, Morgan D.</au><au>Barua, Souptik</au><au>Maj, Tomasz</au><au>Lanfranca, Mirna Perusina</au><au>Delrosario, Lawrence</au><au>Sun, Lei</au><au>Smith, J. Joshua</au><au>D’Angelica, Michael I.</au><au>Shia, Jinru</au><au>Fang, Jiayun M.</au><au>Shi, Jiaqi</au><au>Di Magliano, Marina Pasca</au><au>Zou, Weiping</au><au>Rao, Arvind</au><au>Frankel, Timothy L.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mathematical Modeling of the Metastatic Colorectal Cancer Microenvironment Defines the Importance of Cytotoxic Lymphocyte Infiltration and Presence of PD-L1 on Antigen Presenting Cells</atitle><jtitle>Annals of surgical oncology</jtitle><stitle>Ann Surg Oncol</stitle><addtitle>Ann Surg Oncol</addtitle><date>2019-09-01</date><risdate>2019</risdate><volume>26</volume><issue>9</issue><spage>2821</spage><epage>2830</epage><pages>2821-2830</pages><issn>1068-9265</issn><eissn>1534-4681</eissn><abstract>Background
Although immune-based therapy has proven efficacious for some patients with microsatellite instability (MSI) colon cancers, a majority of patients receive limited benefit. Conversely, select patients with microsatellite stable (MSS) tumors respond to checkpoint blockade, necessitating novel ways to study the immune tumor microenvironment (TME). We used phenotypic and spatial data from infiltrating immune and tumor cells to model cellular mixing to predict disease specific outcomes in patients with colorectal liver metastases.
Methods
Formalin fixed paraffin embedded metastatic colon cancer tissue from 195 patients were subjected to multiplex immunohistochemistry (mfIHC). After phenotyping, the G-function was calculated for each patient and cell type. Data was correlated with clinical outcomes and survival.
Results
High tumor cell to cytotoxic T lymphocyte (TC-CTL) mixing was associated with both a pro-inflammatory and immunosuppressive TME characterized by increased CTL infiltration and PD-L1
+
expression, respectively. Presence and engagement of antigen presenting cells (APC) and helper T cells (Th) were associated with greater TC-CTL mixing and improved 5-year disease specific survival compared to patients with a low degree of mixing (42% vs. 16%,
p
= 0.0275). Comparison of measured mixing to a calculated theoretical random mixing revealed that PD-L1 expression on APCs resulted in an environment where CTLs were non-randomly less associated with TCs, highlighting their biologic significance.
Conclusion
Evaluation of immune interactions within the TME of metastatic colon cancer using mfIHC in combination with mathematical modeling characterized cellular mixing of TCs and CTLs, providing a novel strategy to better predict clinical outcomes while identifying potential candidates for immune based therapies.</abstract><cop>Cham</cop><pub>Springer International Publishing</pub><pmid>31250346</pmid><doi>10.1245/s10434-019-07508-3</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1068-9265 |
| ispartof | Annals of surgical oncology, 2019-09, Vol.26 (9), p.2821-2830 |
| issn | 1068-9265 1534-4681 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6684475 |
| source | MEDLINE; SpringerLink Journals - AutoHoldings |
| subjects | Adenomatous polyposis coli Antigen-presenting cells Antigen-Presenting Cells - immunology Antigens B7-H1 Antigen - immunology B7-H1 Antigen - metabolism Biomarkers, Tumor - immunology Biomarkers, Tumor - metabolism Cell survival Clinical outcomes Colon cancer Colorectal cancer Colorectal carcinoma Colorectal Neoplasms - immunology Colorectal Neoplasms - metabolism Colorectal Neoplasms - pathology Cytotoxicity Female Follow-Up Studies Humans Immune checkpoint Immunohistochemistry Inflammation Liver Neoplasms - immunology Liver Neoplasms - metabolism Liver Neoplasms - secondary Lymphocytes T Lymphocytes, Tumor-Infiltrating - immunology Male Mathematical models Medicine Medicine & Public Health Metastases Metastasis Microsatellite instability Middle Aged Models, Theoretical Oncology Paraffin PD-L1 protein Phenotyping Prognosis Surgery Surgical Oncology Survival Rate T-Lymphocytes, Cytotoxic - immunology Translational Research and Biomarkers Tumor cells Tumor Microenvironment - immunology Tumors |
| title | Mathematical Modeling of the Metastatic Colorectal Cancer Microenvironment Defines the Importance of Cytotoxic Lymphocyte Infiltration and Presence of PD-L1 on Antigen Presenting Cells |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-18T18%3A11%3A09IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Mathematical%20Modeling%20of%20the%20Metastatic%20Colorectal%20Cancer%20Microenvironment%20Defines%20the%20Importance%20of%20Cytotoxic%20Lymphocyte%20Infiltration%20and%20Presence%20of%20PD-L1%20on%20Antigen%20Presenting%20Cells&rft.jtitle=Annals%20of%20surgical%20oncology&rft.au=Lazarus,%20Jenny&rft.date=2019-09-01&rft.volume=26&rft.issue=9&rft.spage=2821&rft.epage=2830&rft.pages=2821-2830&rft.issn=1068-9265&rft.eissn=1534-4681&rft_id=info:doi/10.1245/s10434-019-07508-3&rft_dat=%3Cproquest_pubme%3E931405111%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=227356039&rft_id=info:pmid/31250346&rfr_iscdi=true |