Metformin boosts antitumor immunity and improves prognosis in upfront resected pancreatic cancer: an observational study
Beyond demographic and immune factors, metabolic considerations, particularly metformin's recognized impact in oncology, warrant exploration in treating pancreatic cancer. This study aimed to investigate the influence of metformin on patient survival and its potential correlation with distinct...
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| Veröffentlicht in: | JNCI : Journal of the National Cancer Institute 2024-08, Vol.116 (8), p.1374-1383 |
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| creator | van Eijck, Casper W F Vadgama, Disha van Eijck, Casper H J Wilmink, Johanna W |
| description | Beyond demographic and immune factors, metabolic considerations, particularly metformin's recognized impact in oncology, warrant exploration in treating pancreatic cancer. This study aimed to investigate the influence of metformin on patient survival and its potential correlation with distinct immune profiles in pancreatic ductal adenocarcinoma (PDAC) tumors.
We included 82 upfront resected and 66 gemcitabine-based neoadjuvant chemoradiotherapy (nCRT)-treated patients from the PREOPANC randomized controlled trial (RCT). Transcriptomic NanoString immunoprofiling was performed for a subset of 96 available resected specimens.
Disparities in survival outcomes and immune profiles were apparent between metformin and non-metformin users in upfront resected patients but lacking in nCRT-treated patients. Compared to non-metformin users, upfront resected metformin users showed a higher median overall survival (OS) of 29 vs 14 months and a better 5-year OS rate of 19% vs 5%. Furthermore, metformin use was a favorable prognostic factor for OS in the upfront surgery group (HR = 0.56; 95% CI = 0.32 to 0.99). Transcriptomic data revealed that metformin users significantly underexpressed genes related to pro-tumoral immunity, including monocyte to M2 macrophage polarization and activation. Furthermore, the relative abundance of anti-inflammatory CD163+ MRC1+ M2 macrophages in non-metformin users and immune-activating CD1A+ CD1C+ dendritic cells in metformin users was heightened (P |
| doi_str_mv | 10.1093/jnci/djae070 |
| format | Article |
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We included 82 upfront resected and 66 gemcitabine-based neoadjuvant chemoradiotherapy (nCRT)-treated patients from the PREOPANC randomized controlled trial (RCT). Transcriptomic NanoString immunoprofiling was performed for a subset of 96 available resected specimens.
Disparities in survival outcomes and immune profiles were apparent between metformin and non-metformin users in upfront resected patients but lacking in nCRT-treated patients. Compared to non-metformin users, upfront resected metformin users showed a higher median overall survival (OS) of 29 vs 14 months and a better 5-year OS rate of 19% vs 5%. Furthermore, metformin use was a favorable prognostic factor for OS in the upfront surgery group (HR = 0.56; 95% CI = 0.32 to 0.99). Transcriptomic data revealed that metformin users significantly underexpressed genes related to pro-tumoral immunity, including monocyte to M2 macrophage polarization and activation. Furthermore, the relative abundance of anti-inflammatory CD163+ MRC1+ M2 macrophages in non-metformin users and immune-activating CD1A+ CD1C+ dendritic cells in metformin users was heightened (P < .001).
This study unveils immune profile changes resulting from metformin use in upfront resected pancreatic cancer patients, possibly contributing to prolonged survival outcomes. Specifically, metformin use may decrease the abundance and activity of pro-tumoral M2 macrophages and increase the recruitment and function of tumor-resolving DCs, favoring antitumor immunity.[PREOPANC trial EudraCT: 2012-003181-40].</description><identifier>ISSN: 0027-8874</identifier><identifier>ISSN: 1460-2105</identifier><identifier>EISSN: 1460-2105</identifier><identifier>DOI: 10.1093/jnci/djae070</identifier><identifier>PMID: 38530777</identifier><language>eng</language><publisher>United States: Oxford University Press</publisher><subject>Aged ; Carcinoma, Pancreatic Ductal - drug therapy ; Carcinoma, Pancreatic Ductal - immunology ; Carcinoma, Pancreatic Ductal - mortality ; Carcinoma, Pancreatic Ductal - surgery ; Carcinoma, Pancreatic Ductal - therapy ; Deoxycytidine - administration & dosage ; Deoxycytidine - analogs & derivatives ; Deoxycytidine - therapeutic use ; Early Career Investigator Research ; Female ; Gemcitabine ; Humans ; Hypoglycemic Agents - therapeutic use ; Male ; Metformin - pharmacology ; Metformin - therapeutic use ; Middle Aged ; Neoadjuvant Therapy - methods ; Pancreatic Neoplasms - drug therapy ; Pancreatic Neoplasms - immunology ; Pancreatic Neoplasms - mortality ; Pancreatic Neoplasms - surgery ; Prognosis</subject><ispartof>JNCI : Journal of the National Cancer Institute, 2024-08, Vol.116 (8), p.1374-1383</ispartof><rights>The Author(s) 2024. Published by Oxford University Press.</rights><rights>The Author(s) 2024. Published by Oxford University Press. 2024</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c272t-8a2270475dbdaae5fb5a0eaa49b3c171516d8e903dfa0c1ce5e111b70d3b09d33</cites><orcidid>0000-0002-9511-2157</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27903,27904</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38530777$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>van Eijck, Casper W F</creatorcontrib><creatorcontrib>Vadgama, Disha</creatorcontrib><creatorcontrib>van Eijck, Casper H J</creatorcontrib><creatorcontrib>Wilmink, Johanna W</creatorcontrib><creatorcontrib>Dutch Pancreatic Cancer Group (DPCG)</creatorcontrib><creatorcontrib>for the Dutch Pancreatic Cancer Group (DPCG)</creatorcontrib><title>Metformin boosts antitumor immunity and improves prognosis in upfront resected pancreatic cancer: an observational study</title><title>JNCI : Journal of the National Cancer Institute</title><addtitle>J Natl Cancer Inst</addtitle><description>Beyond demographic and immune factors, metabolic considerations, particularly metformin's recognized impact in oncology, warrant exploration in treating pancreatic cancer. This study aimed to investigate the influence of metformin on patient survival and its potential correlation with distinct immune profiles in pancreatic ductal adenocarcinoma (PDAC) tumors.
We included 82 upfront resected and 66 gemcitabine-based neoadjuvant chemoradiotherapy (nCRT)-treated patients from the PREOPANC randomized controlled trial (RCT). Transcriptomic NanoString immunoprofiling was performed for a subset of 96 available resected specimens.
Disparities in survival outcomes and immune profiles were apparent between metformin and non-metformin users in upfront resected patients but lacking in nCRT-treated patients. Compared to non-metformin users, upfront resected metformin users showed a higher median overall survival (OS) of 29 vs 14 months and a better 5-year OS rate of 19% vs 5%. Furthermore, metformin use was a favorable prognostic factor for OS in the upfront surgery group (HR = 0.56; 95% CI = 0.32 to 0.99). Transcriptomic data revealed that metformin users significantly underexpressed genes related to pro-tumoral immunity, including monocyte to M2 macrophage polarization and activation. Furthermore, the relative abundance of anti-inflammatory CD163+ MRC1+ M2 macrophages in non-metformin users and immune-activating CD1A+ CD1C+ dendritic cells in metformin users was heightened (P < .001).
This study unveils immune profile changes resulting from metformin use in upfront resected pancreatic cancer patients, possibly contributing to prolonged survival outcomes. Specifically, metformin use may decrease the abundance and activity of pro-tumoral M2 macrophages and increase the recruitment and function of tumor-resolving DCs, favoring antitumor immunity.[PREOPANC trial EudraCT: 2012-003181-40].</description><subject>Aged</subject><subject>Carcinoma, Pancreatic Ductal - drug therapy</subject><subject>Carcinoma, Pancreatic Ductal - immunology</subject><subject>Carcinoma, Pancreatic Ductal - mortality</subject><subject>Carcinoma, Pancreatic Ductal - surgery</subject><subject>Carcinoma, Pancreatic Ductal - therapy</subject><subject>Deoxycytidine - administration & dosage</subject><subject>Deoxycytidine - analogs & derivatives</subject><subject>Deoxycytidine - therapeutic use</subject><subject>Early Career Investigator Research</subject><subject>Female</subject><subject>Gemcitabine</subject><subject>Humans</subject><subject>Hypoglycemic Agents - therapeutic use</subject><subject>Male</subject><subject>Metformin - pharmacology</subject><subject>Metformin - therapeutic use</subject><subject>Middle Aged</subject><subject>Neoadjuvant Therapy - methods</subject><subject>Pancreatic Neoplasms - drug therapy</subject><subject>Pancreatic Neoplasms - immunology</subject><subject>Pancreatic Neoplasms - mortality</subject><subject>Pancreatic Neoplasms - surgery</subject><subject>Prognosis</subject><issn>0027-8874</issn><issn>1460-2105</issn><issn>1460-2105</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVUU1v1DAQtRCILoUbZ-Qjh4aO42SdcEFVxUelIi5wtib2pHiV2MF2Vt1_j1ddKjqX-XrvzUiPsbcCPgjo5eXOG3dpd0ig4BnbiGYLVS2gfc42ALWquk41Z-xVSjso0dfNS3Ymu1aCUmrD7r9THkOcnedDCCknjj67vM4hcjfPq3f5UEa2NEsMe0q8pDsfkku8cNZljMFnHimRyWT5gt5EwuwMN6Wk-LGweRgSxX2ZBo8TT3m1h9fsxYhTojenfM5-ffn88_pbdfvj68311W1lalXnqsO6VtCo1g4WkdpxaBEIsekHaYQSrdjajnqQdkQwwlBLQohBgZUD9FbKc_bpQXdZh5msIZ8jTnqJbsZ40AGdfrrx7re-C3sthIROdEeF9yeFGP6slLKeXTI0TegprElLANnIvtvWBXrxADUxpBRpfLwjQB_d0ke39MmtAn_3_2-P4H_2yL-6bpdC</recordid><startdate>20240801</startdate><enddate>20240801</enddate><creator>van Eijck, Casper W F</creator><creator>Vadgama, Disha</creator><creator>van Eijck, Casper H J</creator><creator>Wilmink, Johanna W</creator><general>Oxford University Press</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><orcidid>https://orcid.org/0000-0002-9511-2157</orcidid></search><sort><creationdate>20240801</creationdate><title>Metformin boosts antitumor immunity and improves prognosis in upfront resected pancreatic cancer: an observational study</title><author>van Eijck, Casper W F ; Vadgama, Disha ; van Eijck, Casper H J ; Wilmink, Johanna W</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c272t-8a2270475dbdaae5fb5a0eaa49b3c171516d8e903dfa0c1ce5e111b70d3b09d33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Aged</topic><topic>Carcinoma, Pancreatic Ductal - drug therapy</topic><topic>Carcinoma, Pancreatic Ductal - immunology</topic><topic>Carcinoma, Pancreatic Ductal - mortality</topic><topic>Carcinoma, Pancreatic Ductal - surgery</topic><topic>Carcinoma, Pancreatic Ductal - therapy</topic><topic>Deoxycytidine - administration & dosage</topic><topic>Deoxycytidine - analogs & derivatives</topic><topic>Deoxycytidine - therapeutic use</topic><topic>Early Career Investigator Research</topic><topic>Female</topic><topic>Gemcitabine</topic><topic>Humans</topic><topic>Hypoglycemic Agents - therapeutic use</topic><topic>Male</topic><topic>Metformin - pharmacology</topic><topic>Metformin - therapeutic use</topic><topic>Middle Aged</topic><topic>Neoadjuvant Therapy - methods</topic><topic>Pancreatic Neoplasms - drug therapy</topic><topic>Pancreatic Neoplasms - immunology</topic><topic>Pancreatic Neoplasms - mortality</topic><topic>Pancreatic Neoplasms - surgery</topic><topic>Prognosis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>van Eijck, Casper W F</creatorcontrib><creatorcontrib>Vadgama, Disha</creatorcontrib><creatorcontrib>van Eijck, Casper H J</creatorcontrib><creatorcontrib>Wilmink, Johanna W</creatorcontrib><creatorcontrib>Dutch Pancreatic Cancer Group (DPCG)</creatorcontrib><creatorcontrib>for the Dutch Pancreatic Cancer Group (DPCG)</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>JNCI : Journal of the National Cancer Institute</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>van Eijck, Casper W F</au><au>Vadgama, Disha</au><au>van Eijck, Casper H J</au><au>Wilmink, Johanna W</au><aucorp>Dutch Pancreatic Cancer Group (DPCG)</aucorp><aucorp>for the Dutch Pancreatic Cancer Group (DPCG)</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Metformin boosts antitumor immunity and improves prognosis in upfront resected pancreatic cancer: an observational study</atitle><jtitle>JNCI : Journal of the National Cancer Institute</jtitle><addtitle>J Natl Cancer Inst</addtitle><date>2024-08-01</date><risdate>2024</risdate><volume>116</volume><issue>8</issue><spage>1374</spage><epage>1383</epage><pages>1374-1383</pages><issn>0027-8874</issn><issn>1460-2105</issn><eissn>1460-2105</eissn><abstract>Beyond demographic and immune factors, metabolic considerations, particularly metformin's recognized impact in oncology, warrant exploration in treating pancreatic cancer. This study aimed to investigate the influence of metformin on patient survival and its potential correlation with distinct immune profiles in pancreatic ductal adenocarcinoma (PDAC) tumors.
We included 82 upfront resected and 66 gemcitabine-based neoadjuvant chemoradiotherapy (nCRT)-treated patients from the PREOPANC randomized controlled trial (RCT). Transcriptomic NanoString immunoprofiling was performed for a subset of 96 available resected specimens.
Disparities in survival outcomes and immune profiles were apparent between metformin and non-metformin users in upfront resected patients but lacking in nCRT-treated patients. Compared to non-metformin users, upfront resected metformin users showed a higher median overall survival (OS) of 29 vs 14 months and a better 5-year OS rate of 19% vs 5%. Furthermore, metformin use was a favorable prognostic factor for OS in the upfront surgery group (HR = 0.56; 95% CI = 0.32 to 0.99). Transcriptomic data revealed that metformin users significantly underexpressed genes related to pro-tumoral immunity, including monocyte to M2 macrophage polarization and activation. Furthermore, the relative abundance of anti-inflammatory CD163+ MRC1+ M2 macrophages in non-metformin users and immune-activating CD1A+ CD1C+ dendritic cells in metformin users was heightened (P < .001).
This study unveils immune profile changes resulting from metformin use in upfront resected pancreatic cancer patients, possibly contributing to prolonged survival outcomes. Specifically, metformin use may decrease the abundance and activity of pro-tumoral M2 macrophages and increase the recruitment and function of tumor-resolving DCs, favoring antitumor immunity.[PREOPANC trial EudraCT: 2012-003181-40].</abstract><cop>United States</cop><pub>Oxford University Press</pub><pmid>38530777</pmid><doi>10.1093/jnci/djae070</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0002-9511-2157</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Aged Carcinoma, Pancreatic Ductal - drug therapy Carcinoma, Pancreatic Ductal - immunology Carcinoma, Pancreatic Ductal - mortality Carcinoma, Pancreatic Ductal - surgery Carcinoma, Pancreatic Ductal - therapy Deoxycytidine - administration & dosage Deoxycytidine - analogs & derivatives Deoxycytidine - therapeutic use Early Career Investigator Research Female Gemcitabine Humans Hypoglycemic Agents - therapeutic use Male Metformin - pharmacology Metformin - therapeutic use Middle Aged Neoadjuvant Therapy - methods Pancreatic Neoplasms - drug therapy Pancreatic Neoplasms - immunology Pancreatic Neoplasms - mortality Pancreatic Neoplasms - surgery Prognosis |
| title | Metformin boosts antitumor immunity and improves prognosis in upfront resected pancreatic cancer: an observational study |
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