Pericyte stem cells induce Ly6G+ cell accumulation and immunotherapy resistance in pancreatic cancer
We report the identification of a cell population that shares pericyte, stromal and stemness features, does not harbor the Kras G12D mutation and drives tumoral growth in vitro and in vivo . We term these cells pericyte stem cells (PeSCs) and define them as CD45 − EPCAM − CD29 + CD106 + CD24 + CD44...
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| creator | Wu, Zhichong Thierry, Kevin Bachy, Sophie Zhang, Xinyi Gamradt, Pia Hernandez‐Vargas, Hector Mikaelian, Ivan Tonon, Laurie Pommier, Roxanne Zhao, Yajie Bertolino, Philippe Hennino, Ana |
| description | We report the identification of a cell population that shares pericyte, stromal and stemness features, does not harbor the
Kras
G12D
mutation and drives tumoral growth
in vitro
and
in vivo
. We term these cells pericyte stem cells (PeSCs) and define them as CD45
−
EPCAM
−
CD29
+
CD106
+
CD24
+
CD44
+
cells. We perform studies with
p48
‐Cre;
Kras
G12D
(KC),
pdx1
‐Cre;
Kras
G12D
;
Ink4a
/
Arf
fl/fl
(KIC) and
pdx1
‐Cre;
Kras
G12D
;
p53
R172H
(KPC) and tumor tissues from PDAC and chronic pancreatitis patients. We also perform single‐cell RNAseq analysis and reveal a unique signature of PeSC. Under steady‐state conditions, PeSCs are barely detectable in the pancreas but present in the neoplastic microenvironment both in humans and mice. The coinjection of PeSCs and tumor epithelial cells leads to increased tumor growth, differentiation of Ly6G
+
myeloid‐derived suppressor cells, and a decreased amount of F4/80
+
macrophages and CD11c
+
dendritic cells. This population induces resistance to anti‐PD‐1 immunotherapy when coinjected with epithelial tumor cells. Our data reveal the existence of a cell population that instructs immunosuppressive myeloid cell responses to bypass PD‐1 targeting and thus suggest potential new approaches for overcoming resistance to immunotherapy in clinical settings.
Synopsis
Pericyte stem cells (PeSCs) represent a newly identified cell population that shares pericyte, stromal and stemness features and drives tumoral growth in pancreatic cancer. This study reports on the role of these cells within the tumor microenvironment.
PeSCs are barely detectable in the pancreas under steady‐state conditions.
PeSC are present in the neoplastic microenvironment in pancreatic cancer both in humans and mice.
Co‐injection of PeSCs and tumor epithelial cells increases the differentiation of Ly6G
+
myeloid‐derived suppressor cells.
PeSCs instruct immunosuppressive myeloid cell responses to bypass PD‐1 targeting.
Graphical Abstract
Pericyte stem cells (PeSCs) represent a newly identified cell population that shares pericyte, stromal and stemness features and drives tumoral growth in pancreatic cancer. This study reports on the role of these cells within the tumor microenvironment. |
| doi_str_mv | 10.15252/embr.202256524 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_10074138</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2778978660</sourcerecordid><originalsourceid>FETCH-LOGICAL-c5484-55f6ec8feca8e6e9422e277d791ee2c6c9e2432798d3d0df9051ac96f8fe53513</originalsourceid><addsrcrecordid>eNqFkc1rFTEUxQdRbG1du5OAG0Vem2Ty2Y3UUlvhFUUU3IU0c6cvZSbzTGYq89-b6TyfbUG6Srj5nXNP7i2KVwQfEE45PYT2Mh5QTCkXnLInxS5hQi9KItXTzZ1S8nOneJHSNcaYa6meFzulUFki5G5RfYXo3dgDSj20yEHTJORDNThAy1Gcvb8tIevc0A6N7X0XkA0V8m07hK5fQbTrEUVIPvU2ZJEPaJ0vETLrkJtqcb94VtsmwcvNuVf8-HT6_eR8sfxy9vnkeLlwnCm24LwW4FQNzioQoBmlQKWspCYA1AmngbKSSq2qssJVrTEn1mlRZwkvOSn3ig-z73q4bKFyEPpoG7OOvrVxNJ315v5L8Ctz1d0YgrFkpFTZ4d3ssHqgOz9emqmGGWYS0_Jm6vZ20y12vwZIvWl9mqZlA3RDMjm6yuMWAmf0zQP0uhtiyLPIlOZEYqKn5ocz5WKXUoR6m4Bgc7tuM63bbNedFa_vfnjL_91vBo5m4LdvYHzMz5xefPx21x3P4pR14Qriv9T_C_QHtZ3Hvg</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2795170198</pqid></control><display><type>article</type><title>Pericyte stem cells induce Ly6G+ cell accumulation and immunotherapy resistance in pancreatic cancer</title><source>Wiley Free Content</source><source>MEDLINE</source><source>Wiley Online Library Journals Frontfile Complete</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>PubMed Central</source><source>Springer Nature OA Free Journals</source><creator>Wu, Zhichong ; Thierry, Kevin ; Bachy, Sophie ; Zhang, Xinyi ; Gamradt, Pia ; Hernandez‐Vargas, Hector ; Mikaelian, Ivan ; Tonon, Laurie ; Pommier, Roxanne ; Zhao, Yajie ; Bertolino, Philippe ; Hennino, Ana</creator><creatorcontrib>Wu, Zhichong ; Thierry, Kevin ; Bachy, Sophie ; Zhang, Xinyi ; Gamradt, Pia ; Hernandez‐Vargas, Hector ; Mikaelian, Ivan ; Tonon, Laurie ; Pommier, Roxanne ; Zhao, Yajie ; Bertolino, Philippe ; Hennino, Ana</creatorcontrib><description>We report the identification of a cell population that shares pericyte, stromal and stemness features, does not harbor the
Kras
G12D
mutation and drives tumoral growth
in vitro
and
in vivo
. We term these cells pericyte stem cells (PeSCs) and define them as CD45
−
EPCAM
−
CD29
+
CD106
+
CD24
+
CD44
+
cells. We perform studies with
p48
‐Cre;
Kras
G12D
(KC),
pdx1
‐Cre;
Kras
G12D
;
Ink4a
/
Arf
fl/fl
(KIC) and
pdx1
‐Cre;
Kras
G12D
;
p53
R172H
(KPC) and tumor tissues from PDAC and chronic pancreatitis patients. We also perform single‐cell RNAseq analysis and reveal a unique signature of PeSC. Under steady‐state conditions, PeSCs are barely detectable in the pancreas but present in the neoplastic microenvironment both in humans and mice. The coinjection of PeSCs and tumor epithelial cells leads to increased tumor growth, differentiation of Ly6G
+
myeloid‐derived suppressor cells, and a decreased amount of F4/80
+
macrophages and CD11c
+
dendritic cells. This population induces resistance to anti‐PD‐1 immunotherapy when coinjected with epithelial tumor cells. Our data reveal the existence of a cell population that instructs immunosuppressive myeloid cell responses to bypass PD‐1 targeting and thus suggest potential new approaches for overcoming resistance to immunotherapy in clinical settings.
Synopsis
Pericyte stem cells (PeSCs) represent a newly identified cell population that shares pericyte, stromal and stemness features and drives tumoral growth in pancreatic cancer. This study reports on the role of these cells within the tumor microenvironment.
PeSCs are barely detectable in the pancreas under steady‐state conditions.
PeSC are present in the neoplastic microenvironment in pancreatic cancer both in humans and mice.
Co‐injection of PeSCs and tumor epithelial cells increases the differentiation of Ly6G
+
myeloid‐derived suppressor cells.
PeSCs instruct immunosuppressive myeloid cell responses to bypass PD‐1 targeting.
Graphical Abstract
Pericyte stem cells (PeSCs) represent a newly identified cell population that shares pericyte, stromal and stemness features and drives tumoral growth in pancreatic cancer. This study reports on the role of these cells within the tumor microenvironment.</description><identifier>ISSN: 1469-221X</identifier><identifier>EISSN: 1469-3178</identifier><identifier>DOI: 10.15252/embr.202256524</identifier><identifier>PMID: 36802267</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>Animals ; Cancer ; Carcinoma, Pancreatic Ductal - genetics ; Carcinoma, Pancreatic Ductal - pathology ; Carcinoma, Pancreatic Ductal - therapy ; CD11c antigen ; CD29 antigen ; CD44 antigen ; CD45 antigen ; Cell differentiation ; Coinjection ; Dendritic cells ; Differentiation ; Drug resistance ; EMBO03 ; EMBO19 ; EMBO34 ; Epithelial cells ; Epithelium ; Humans ; Immunotherapy ; INK4 protein ; Life Sciences ; Macrophages ; Mice ; myeloid‐derived suppressor cells ; Pancreas ; Pancreatic cancer ; Pancreatic Neoplasms ; Pancreatic Neoplasms - genetics ; Pancreatitis ; PD‐1 therapy ; pericyte stem cells ; Pericytes ; Proto-Oncogene Proteins p21(ras) ; Stem Cells ; Suppressor cells ; Tumor cells ; Tumor Microenvironment ; Tumors</subject><ispartof>EMBO reports, 2023-04, Vol.24 (4), p.e56524-n/a</ispartof><rights>The Author(s) 2023</rights><rights>2023 The Authors. Published under the terms of the CC BY NC ND 4.0 license</rights><rights>2023 The Authors. Published under the terms of the CC BY NC ND 4.0 license.</rights><rights>2023. This article is published under http://creativecommons.org/licenses/by-nc-nd/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5484-55f6ec8feca8e6e9422e277d791ee2c6c9e2432798d3d0df9051ac96f8fe53513</citedby><cites>FETCH-LOGICAL-c5484-55f6ec8feca8e6e9422e277d791ee2c6c9e2432798d3d0df9051ac96f8fe53513</cites><orcidid>0000-0003-0123-3124 ; 0000-0002-6166-755X ; 0000-0001-6045-2103 ; 0000-0002-2619-8559 ; 0000-0001-8064-8269 ; 0000-0001-5222-3570 ; 0009-0005-8794-7276</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/PMC10074138/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10074138/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,1411,1427,27901,27902,41096,42165,45550,45551,46384,46808,51551,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/36802267$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://hal.science/hal-04047023$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Wu, Zhichong</creatorcontrib><creatorcontrib>Thierry, Kevin</creatorcontrib><creatorcontrib>Bachy, Sophie</creatorcontrib><creatorcontrib>Zhang, Xinyi</creatorcontrib><creatorcontrib>Gamradt, Pia</creatorcontrib><creatorcontrib>Hernandez‐Vargas, Hector</creatorcontrib><creatorcontrib>Mikaelian, Ivan</creatorcontrib><creatorcontrib>Tonon, Laurie</creatorcontrib><creatorcontrib>Pommier, Roxanne</creatorcontrib><creatorcontrib>Zhao, Yajie</creatorcontrib><creatorcontrib>Bertolino, Philippe</creatorcontrib><creatorcontrib>Hennino, Ana</creatorcontrib><title>Pericyte stem cells induce Ly6G+ cell accumulation and immunotherapy resistance in pancreatic cancer</title><title>EMBO reports</title><addtitle>EMBO Rep</addtitle><addtitle>EMBO Rep</addtitle><description>We report the identification of a cell population that shares pericyte, stromal and stemness features, does not harbor the
Kras
G12D
mutation and drives tumoral growth
in vitro
and
in vivo
. We term these cells pericyte stem cells (PeSCs) and define them as CD45
−
EPCAM
−
CD29
+
CD106
+
CD24
+
CD44
+
cells. We perform studies with
p48
‐Cre;
Kras
G12D
(KC),
pdx1
‐Cre;
Kras
G12D
;
Ink4a
/
Arf
fl/fl
(KIC) and
pdx1
‐Cre;
Kras
G12D
;
p53
R172H
(KPC) and tumor tissues from PDAC and chronic pancreatitis patients. We also perform single‐cell RNAseq analysis and reveal a unique signature of PeSC. Under steady‐state conditions, PeSCs are barely detectable in the pancreas but present in the neoplastic microenvironment both in humans and mice. The coinjection of PeSCs and tumor epithelial cells leads to increased tumor growth, differentiation of Ly6G
+
myeloid‐derived suppressor cells, and a decreased amount of F4/80
+
macrophages and CD11c
+
dendritic cells. This population induces resistance to anti‐PD‐1 immunotherapy when coinjected with epithelial tumor cells. Our data reveal the existence of a cell population that instructs immunosuppressive myeloid cell responses to bypass PD‐1 targeting and thus suggest potential new approaches for overcoming resistance to immunotherapy in clinical settings.
Synopsis
Pericyte stem cells (PeSCs) represent a newly identified cell population that shares pericyte, stromal and stemness features and drives tumoral growth in pancreatic cancer. This study reports on the role of these cells within the tumor microenvironment.
PeSCs are barely detectable in the pancreas under steady‐state conditions.
PeSC are present in the neoplastic microenvironment in pancreatic cancer both in humans and mice.
Co‐injection of PeSCs and tumor epithelial cells increases the differentiation of Ly6G
+
myeloid‐derived suppressor cells.
PeSCs instruct immunosuppressive myeloid cell responses to bypass PD‐1 targeting.
Graphical Abstract
Pericyte stem cells (PeSCs) represent a newly identified cell population that shares pericyte, stromal and stemness features and drives tumoral growth in pancreatic cancer. This study reports on the role of these cells within the tumor microenvironment.</description><subject>Animals</subject><subject>Cancer</subject><subject>Carcinoma, Pancreatic Ductal - genetics</subject><subject>Carcinoma, Pancreatic Ductal - pathology</subject><subject>Carcinoma, Pancreatic Ductal - therapy</subject><subject>CD11c antigen</subject><subject>CD29 antigen</subject><subject>CD44 antigen</subject><subject>CD45 antigen</subject><subject>Cell differentiation</subject><subject>Coinjection</subject><subject>Dendritic cells</subject><subject>Differentiation</subject><subject>Drug resistance</subject><subject>EMBO03</subject><subject>EMBO19</subject><subject>EMBO34</subject><subject>Epithelial cells</subject><subject>Epithelium</subject><subject>Humans</subject><subject>Immunotherapy</subject><subject>INK4 protein</subject><subject>Life Sciences</subject><subject>Macrophages</subject><subject>Mice</subject><subject>myeloid‐derived suppressor cells</subject><subject>Pancreas</subject><subject>Pancreatic cancer</subject><subject>Pancreatic Neoplasms</subject><subject>Pancreatic Neoplasms - genetics</subject><subject>Pancreatitis</subject><subject>PD‐1 therapy</subject><subject>pericyte stem cells</subject><subject>Pericytes</subject><subject>Proto-Oncogene Proteins p21(ras)</subject><subject>Stem Cells</subject><subject>Suppressor cells</subject><subject>Tumor cells</subject><subject>Tumor Microenvironment</subject><subject>Tumors</subject><issn>1469-221X</issn><issn>1469-3178</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>24P</sourceid><sourceid>EIF</sourceid><recordid>eNqFkc1rFTEUxQdRbG1du5OAG0Vem2Ty2Y3UUlvhFUUU3IU0c6cvZSbzTGYq89-b6TyfbUG6Srj5nXNP7i2KVwQfEE45PYT2Mh5QTCkXnLInxS5hQi9KItXTzZ1S8nOneJHSNcaYa6meFzulUFki5G5RfYXo3dgDSj20yEHTJORDNThAy1Gcvb8tIevc0A6N7X0XkA0V8m07hK5fQbTrEUVIPvU2ZJEPaJ0vETLrkJtqcb94VtsmwcvNuVf8-HT6_eR8sfxy9vnkeLlwnCm24LwW4FQNzioQoBmlQKWspCYA1AmngbKSSq2qssJVrTEn1mlRZwkvOSn3ig-z73q4bKFyEPpoG7OOvrVxNJ315v5L8Ctz1d0YgrFkpFTZ4d3ssHqgOz9emqmGGWYS0_Jm6vZ20y12vwZIvWl9mqZlA3RDMjm6yuMWAmf0zQP0uhtiyLPIlOZEYqKn5ocz5WKXUoR6m4Bgc7tuM63bbNedFa_vfnjL_91vBo5m4LdvYHzMz5xefPx21x3P4pR14Qriv9T_C_QHtZ3Hvg</recordid><startdate>20230405</startdate><enddate>20230405</enddate><creator>Wu, Zhichong</creator><creator>Thierry, Kevin</creator><creator>Bachy, Sophie</creator><creator>Zhang, Xinyi</creator><creator>Gamradt, Pia</creator><creator>Hernandez‐Vargas, Hector</creator><creator>Mikaelian, Ivan</creator><creator>Tonon, Laurie</creator><creator>Pommier, Roxanne</creator><creator>Zhao, Yajie</creator><creator>Bertolino, Philippe</creator><creator>Hennino, Ana</creator><general>Nature Publishing Group UK</general><general>Springer Nature B.V</general><general>EMBO Press</general><general>John Wiley and Sons Inc</general><scope>C6C</scope><scope>24P</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>7QL</scope><scope>7T5</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>1XC</scope><scope>VOOES</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-0123-3124</orcidid><orcidid>https://orcid.org/0000-0002-6166-755X</orcidid><orcidid>https://orcid.org/0000-0001-6045-2103</orcidid><orcidid>https://orcid.org/0000-0002-2619-8559</orcidid><orcidid>https://orcid.org/0000-0001-8064-8269</orcidid><orcidid>https://orcid.org/0000-0001-5222-3570</orcidid><orcidid>https://orcid.org/0009-0005-8794-7276</orcidid></search><sort><creationdate>20230405</creationdate><title>Pericyte stem cells induce Ly6G+ cell accumulation and immunotherapy resistance in pancreatic cancer</title><author>Wu, Zhichong ; Thierry, Kevin ; Bachy, Sophie ; Zhang, Xinyi ; Gamradt, Pia ; Hernandez‐Vargas, Hector ; Mikaelian, Ivan ; Tonon, Laurie ; Pommier, Roxanne ; Zhao, Yajie ; Bertolino, Philippe ; Hennino, Ana</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5484-55f6ec8feca8e6e9422e277d791ee2c6c9e2432798d3d0df9051ac96f8fe53513</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Animals</topic><topic>Cancer</topic><topic>Carcinoma, Pancreatic Ductal - genetics</topic><topic>Carcinoma, Pancreatic Ductal - pathology</topic><topic>Carcinoma, Pancreatic Ductal - therapy</topic><topic>CD11c antigen</topic><topic>CD29 antigen</topic><topic>CD44 antigen</topic><topic>CD45 antigen</topic><topic>Cell differentiation</topic><topic>Coinjection</topic><topic>Dendritic cells</topic><topic>Differentiation</topic><topic>Drug resistance</topic><topic>EMBO03</topic><topic>EMBO19</topic><topic>EMBO34</topic><topic>Epithelial cells</topic><topic>Epithelium</topic><topic>Humans</topic><topic>Immunotherapy</topic><topic>INK4 protein</topic><topic>Life Sciences</topic><topic>Macrophages</topic><topic>Mice</topic><topic>myeloid‐derived suppressor cells</topic><topic>Pancreas</topic><topic>Pancreatic cancer</topic><topic>Pancreatic Neoplasms</topic><topic>Pancreatic Neoplasms - genetics</topic><topic>Pancreatitis</topic><topic>PD‐1 therapy</topic><topic>pericyte stem cells</topic><topic>Pericytes</topic><topic>Proto-Oncogene Proteins p21(ras)</topic><topic>Stem Cells</topic><topic>Suppressor cells</topic><topic>Tumor cells</topic><topic>Tumor Microenvironment</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wu, Zhichong</creatorcontrib><creatorcontrib>Thierry, Kevin</creatorcontrib><creatorcontrib>Bachy, Sophie</creatorcontrib><creatorcontrib>Zhang, Xinyi</creatorcontrib><creatorcontrib>Gamradt, Pia</creatorcontrib><creatorcontrib>Hernandez‐Vargas, Hector</creatorcontrib><creatorcontrib>Mikaelian, Ivan</creatorcontrib><creatorcontrib>Tonon, Laurie</creatorcontrib><creatorcontrib>Pommier, Roxanne</creatorcontrib><creatorcontrib>Zhao, Yajie</creatorcontrib><creatorcontrib>Bertolino, Philippe</creatorcontrib><creatorcontrib>Hennino, Ana</creatorcontrib><collection>Springer Nature OA Free Journals</collection><collection>Wiley Online Library Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Immunology Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>Hyper Article en Ligne (HAL)</collection><collection>Hyper Article en Ligne (HAL) (Open Access)</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>EMBO reports</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wu, Zhichong</au><au>Thierry, Kevin</au><au>Bachy, Sophie</au><au>Zhang, Xinyi</au><au>Gamradt, Pia</au><au>Hernandez‐Vargas, Hector</au><au>Mikaelian, Ivan</au><au>Tonon, Laurie</au><au>Pommier, Roxanne</au><au>Zhao, Yajie</au><au>Bertolino, Philippe</au><au>Hennino, Ana</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Pericyte stem cells induce Ly6G+ cell accumulation and immunotherapy resistance in pancreatic cancer</atitle><jtitle>EMBO reports</jtitle><stitle>EMBO Rep</stitle><addtitle>EMBO Rep</addtitle><date>2023-04-05</date><risdate>2023</risdate><volume>24</volume><issue>4</issue><spage>e56524</spage><epage>n/a</epage><pages>e56524-n/a</pages><issn>1469-221X</issn><eissn>1469-3178</eissn><abstract>We report the identification of a cell population that shares pericyte, stromal and stemness features, does not harbor the
Kras
G12D
mutation and drives tumoral growth
in vitro
and
in vivo
. We term these cells pericyte stem cells (PeSCs) and define them as CD45
−
EPCAM
−
CD29
+
CD106
+
CD24
+
CD44
+
cells. We perform studies with
p48
‐Cre;
Kras
G12D
(KC),
pdx1
‐Cre;
Kras
G12D
;
Ink4a
/
Arf
fl/fl
(KIC) and
pdx1
‐Cre;
Kras
G12D
;
p53
R172H
(KPC) and tumor tissues from PDAC and chronic pancreatitis patients. We also perform single‐cell RNAseq analysis and reveal a unique signature of PeSC. Under steady‐state conditions, PeSCs are barely detectable in the pancreas but present in the neoplastic microenvironment both in humans and mice. The coinjection of PeSCs and tumor epithelial cells leads to increased tumor growth, differentiation of Ly6G
+
myeloid‐derived suppressor cells, and a decreased amount of F4/80
+
macrophages and CD11c
+
dendritic cells. This population induces resistance to anti‐PD‐1 immunotherapy when coinjected with epithelial tumor cells. Our data reveal the existence of a cell population that instructs immunosuppressive myeloid cell responses to bypass PD‐1 targeting and thus suggest potential new approaches for overcoming resistance to immunotherapy in clinical settings.
Synopsis
Pericyte stem cells (PeSCs) represent a newly identified cell population that shares pericyte, stromal and stemness features and drives tumoral growth in pancreatic cancer. This study reports on the role of these cells within the tumor microenvironment.
PeSCs are barely detectable in the pancreas under steady‐state conditions.
PeSC are present in the neoplastic microenvironment in pancreatic cancer both in humans and mice.
Co‐injection of PeSCs and tumor epithelial cells increases the differentiation of Ly6G
+
myeloid‐derived suppressor cells.
PeSCs instruct immunosuppressive myeloid cell responses to bypass PD‐1 targeting.
Graphical Abstract
Pericyte stem cells (PeSCs) represent a newly identified cell population that shares pericyte, stromal and stemness features and drives tumoral growth in pancreatic cancer. This study reports on the role of these cells within the tumor microenvironment.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>36802267</pmid><doi>10.15252/embr.202256524</doi><tpages>33</tpages><orcidid>https://orcid.org/0000-0003-0123-3124</orcidid><orcidid>https://orcid.org/0000-0002-6166-755X</orcidid><orcidid>https://orcid.org/0000-0001-6045-2103</orcidid><orcidid>https://orcid.org/0000-0002-2619-8559</orcidid><orcidid>https://orcid.org/0000-0001-8064-8269</orcidid><orcidid>https://orcid.org/0000-0001-5222-3570</orcidid><orcidid>https://orcid.org/0009-0005-8794-7276</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1469-221X |
| ispartof | EMBO reports, 2023-04, Vol.24 (4), p.e56524-n/a |
| issn | 1469-221X 1469-3178 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_10074138 |
| source | Wiley Free Content; MEDLINE; Wiley Online Library Journals Frontfile Complete; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Springer Nature OA Free Journals |
| subjects | Animals Cancer Carcinoma, Pancreatic Ductal - genetics Carcinoma, Pancreatic Ductal - pathology Carcinoma, Pancreatic Ductal - therapy CD11c antigen CD29 antigen CD44 antigen CD45 antigen Cell differentiation Coinjection Dendritic cells Differentiation Drug resistance EMBO03 EMBO19 EMBO34 Epithelial cells Epithelium Humans Immunotherapy INK4 protein Life Sciences Macrophages Mice myeloid‐derived suppressor cells Pancreas Pancreatic cancer Pancreatic Neoplasms Pancreatic Neoplasms - genetics Pancreatitis PD‐1 therapy pericyte stem cells Pericytes Proto-Oncogene Proteins p21(ras) Stem Cells Suppressor cells Tumor cells Tumor Microenvironment Tumors |
| title | Pericyte stem cells induce Ly6G+ cell accumulation and immunotherapy resistance in pancreatic cancer |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-02T08%3A13%3A00IST&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=Pericyte%20stem%20cells%20induce%20Ly6G+%20cell%20accumulation%20and%20immunotherapy%20resistance%20in%20pancreatic%20cancer&rft.jtitle=EMBO%20reports&rft.au=Wu,%20Zhichong&rft.date=2023-04-05&rft.volume=24&rft.issue=4&rft.spage=e56524&rft.epage=n/a&rft.pages=e56524-n/a&rft.issn=1469-221X&rft.eissn=1469-3178&rft_id=info:doi/10.15252/embr.202256524&rft_dat=%3Cproquest_pubme%3E2778978660%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=2795170198&rft_id=info:pmid/36802267&rfr_iscdi=true |