Tumour DDR1 promotes collagen fibre alignment to instigate immune exclusion
Immune exclusion predicts poor patient outcomes in multiple malignancies, including triple-negative breast cancer (TNBC) 1 . The extracellular matrix (ECM) contributes to immune exclusion 2 . However, strategies to reduce ECM abundance are largely ineffective or generate undesired outcomes 3 , 4 . H...
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| Veröffentlicht in: | Nature (London) 2021-11, Vol.599 (7886), p.673-678 |
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| creator | Sun, Xiujie Wu, Bogang Chiang, Huai-Chin Deng, Hui Zhang, Xiaowen Xiong, Wei Liu, Junquan Rozeboom, Aaron M. Harris, Brent T. Blommaert, Eline Gomez, Antonio Garcia, Roderic Espin Zhou, Yufan Mitra, Payal Prevost, Madeleine Zhang, Deyi Banik, Debarati Isaacs, Claudine Berry, Deborah Lai, Catherine Chaldekas, Krysta Latham, Patricia S. Brantner, Christine A. Popratiloff, Anastas Jin, Victor X. Zhang, Ningyan Hu, Yanfen Pujana, Miguel Angel Curiel, Tyler J. An, Zhiqiang Li, Rong |
| description | Immune exclusion predicts poor patient outcomes in multiple malignancies, including triple-negative breast cancer (TNBC)
1
. The extracellular matrix (ECM) contributes to immune exclusion
2
. However, strategies to reduce ECM abundance are largely ineffective or generate undesired outcomes
3
,
4
. Here we show that discoidin domain receptor 1 (DDR1), a collagen receptor with tyrosine kinase activity
5
, instigates immune exclusion by promoting collagen fibre alignment. Ablation of
Ddr1
in tumours promotes the intratumoral penetration of T cells and obliterates tumour growth in mouse models of TNBC. Supporting this finding, in human TNBC the expression of DDR1 negatively correlates with the intratumoral abundance of anti-tumour T cells. The DDR1 extracellular domain (DDR1-ECD), but not its intracellular kinase domain, is required for immune exclusion. Membrane-untethered DDR1-ECD is sufficient to rescue the growth of
Ddr1
-knockout tumours in immunocompetent hosts. Mechanistically, the binding of DDR1-ECD to collagen enforces aligned collagen fibres and obstructs immune infiltration. ECD-neutralizing antibodies disrupt collagen fibre alignment, mitigate immune exclusion and inhibit tumour growth in immunocompetent hosts. Together, our findings identify a mechanism for immune exclusion and suggest an immunotherapeutic target for increasing immune accessibility through reconfiguration of the tumour ECM.
In mouse models of triple-negative breast cancer, the extracellular domain of the collagen receptor DDR1 has a role in tumour defence against the immune system, by aligning collagen fibres to obstruct immune infiltration. |
| doi_str_mv | 10.1038/s41586-021-04057-2 |
| format | Article |
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1
. The extracellular matrix (ECM) contributes to immune exclusion
2
. However, strategies to reduce ECM abundance are largely ineffective or generate undesired outcomes
3
,
4
. Here we show that discoidin domain receptor 1 (DDR1), a collagen receptor with tyrosine kinase activity
5
, instigates immune exclusion by promoting collagen fibre alignment. Ablation of
Ddr1
in tumours promotes the intratumoral penetration of T cells and obliterates tumour growth in mouse models of TNBC. Supporting this finding, in human TNBC the expression of DDR1 negatively correlates with the intratumoral abundance of anti-tumour T cells. The DDR1 extracellular domain (DDR1-ECD), but not its intracellular kinase domain, is required for immune exclusion. Membrane-untethered DDR1-ECD is sufficient to rescue the growth of
Ddr1
-knockout tumours in immunocompetent hosts. Mechanistically, the binding of DDR1-ECD to collagen enforces aligned collagen fibres and obstructs immune infiltration. ECD-neutralizing antibodies disrupt collagen fibre alignment, mitigate immune exclusion and inhibit tumour growth in immunocompetent hosts. Together, our findings identify a mechanism for immune exclusion and suggest an immunotherapeutic target for increasing immune accessibility through reconfiguration of the tumour ECM.
In mouse models of triple-negative breast cancer, the extracellular domain of the collagen receptor DDR1 has a role in tumour defence against the immune system, by aligning collagen fibres to obstruct immune infiltration.</description><identifier>ISSN: 0028-0836</identifier><identifier>EISSN: 1476-4687</identifier><identifier>DOI: 10.1038/s41586-021-04057-2</identifier><identifier>PMID: 34732895</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/1 ; 13/106 ; 13/109 ; 13/31 ; 13/44 ; 13/51 ; 14 ; 14/19 ; 14/63 ; 38 ; 38/39 ; 38/70 ; 38/77 ; 38/90 ; 42 ; 42/41 ; 45 ; 59 ; 631/67/1347 ; 631/67/327 ; 64 ; 64/60 ; 82 ; 82/29 ; 82/51 ; 82/80 ; 82/83 ; 96 ; 96/21 ; 96/31 ; 96/95 ; Ablation ; Alignment ; Animal models ; Animals ; Antibodies ; Breast cancer ; Cell Line, Tumor ; Collagen ; Collagen - metabolism ; Discoidin Domain Receptor 1 - antagonists & inhibitors ; Discoidin Domain Receptor 1 - deficiency ; Discoidin Domain Receptor 1 - genetics ; Discoidin Domain Receptor 1 - metabolism ; Disease Models, Animal ; Domains ; Extracellular matrix ; Extracellular Matrix - immunology ; Extracellular Matrix - metabolism ; Female ; Fibers ; Gene Deletion ; Gene expression ; Gene Knockout Techniques ; Genetic aspects ; Health aspects ; Humanities and Social Sciences ; Humans ; Immune response ; Immunocompetence ; Immunocompetence - immunology ; Immunotherapy ; Kinases ; Lymphocytes ; Lymphocytes T ; Metastases ; Mice ; multidisciplinary ; Physiological aspects ; Protein-tyrosine kinase ; Receptors ; Reconfiguration ; Science ; Science (multidisciplinary) ; Signal transduction ; T-Lymphocytes - cytology ; T-Lymphocytes - immunology ; Triple Negative Breast Neoplasms - immunology ; Triple Negative Breast Neoplasms - metabolism ; Triple Negative Breast Neoplasms - therapy ; Tumor Escape ; Tumors ; Tyrosine</subject><ispartof>Nature (London), 2021-11, Vol.599 (7886), p.673-678</ispartof><rights>The Author(s), under exclusive licence to Springer Nature Limited 2021</rights><rights>2021. The Author(s), under exclusive licence to Springer Nature Limited.</rights><rights>COPYRIGHT 2021 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Nov 25, 2021</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c640t-76d5f81a1ae772d632de792c951b74d3ba85889adb3824acf2eb1a5586eefd643</citedby><cites>FETCH-LOGICAL-c640t-76d5f81a1ae772d632de792c951b74d3ba85889adb3824acf2eb1a5586eefd643</cites><orcidid>0000-0002-8765-3471 ; 0000-0001-6962-9411 ; 0000-0003-2782-9444 ; 0000-0003-3222-4044 ; 0000-0003-0040-5158 ; 0000-0002-7616-3362 ; 0000-0002-4348-2180 ; 0000-0001-5308-981X ; 0000-0003-2494-0964 ; 0000-0002-8385-433X ; 0000-0001-9309-2335 ; 0000-0003-1654-198X ; 0000-0002-6471-6580</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/s41586-021-04057-2$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/s41586-021-04057-2$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>230,314,780,784,885,27923,27924,41487,42556,51318</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34732895$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sun, Xiujie</creatorcontrib><creatorcontrib>Wu, Bogang</creatorcontrib><creatorcontrib>Chiang, Huai-Chin</creatorcontrib><creatorcontrib>Deng, Hui</creatorcontrib><creatorcontrib>Zhang, Xiaowen</creatorcontrib><creatorcontrib>Xiong, Wei</creatorcontrib><creatorcontrib>Liu, Junquan</creatorcontrib><creatorcontrib>Rozeboom, Aaron M.</creatorcontrib><creatorcontrib>Harris, Brent T.</creatorcontrib><creatorcontrib>Blommaert, Eline</creatorcontrib><creatorcontrib>Gomez, Antonio</creatorcontrib><creatorcontrib>Garcia, Roderic Espin</creatorcontrib><creatorcontrib>Zhou, Yufan</creatorcontrib><creatorcontrib>Mitra, Payal</creatorcontrib><creatorcontrib>Prevost, Madeleine</creatorcontrib><creatorcontrib>Zhang, Deyi</creatorcontrib><creatorcontrib>Banik, Debarati</creatorcontrib><creatorcontrib>Isaacs, Claudine</creatorcontrib><creatorcontrib>Berry, Deborah</creatorcontrib><creatorcontrib>Lai, Catherine</creatorcontrib><creatorcontrib>Chaldekas, Krysta</creatorcontrib><creatorcontrib>Latham, Patricia S.</creatorcontrib><creatorcontrib>Brantner, Christine A.</creatorcontrib><creatorcontrib>Popratiloff, Anastas</creatorcontrib><creatorcontrib>Jin, Victor X.</creatorcontrib><creatorcontrib>Zhang, Ningyan</creatorcontrib><creatorcontrib>Hu, Yanfen</creatorcontrib><creatorcontrib>Pujana, Miguel Angel</creatorcontrib><creatorcontrib>Curiel, Tyler J.</creatorcontrib><creatorcontrib>An, Zhiqiang</creatorcontrib><creatorcontrib>Li, Rong</creatorcontrib><title>Tumour DDR1 promotes collagen fibre alignment to instigate immune exclusion</title><title>Nature (London)</title><addtitle>Nature</addtitle><addtitle>Nature</addtitle><description>Immune exclusion predicts poor patient outcomes in multiple malignancies, including triple-negative breast cancer (TNBC)
1
. The extracellular matrix (ECM) contributes to immune exclusion
2
. However, strategies to reduce ECM abundance are largely ineffective or generate undesired outcomes
3
,
4
. Here we show that discoidin domain receptor 1 (DDR1), a collagen receptor with tyrosine kinase activity
5
, instigates immune exclusion by promoting collagen fibre alignment. Ablation of
Ddr1
in tumours promotes the intratumoral penetration of T cells and obliterates tumour growth in mouse models of TNBC. Supporting this finding, in human TNBC the expression of DDR1 negatively correlates with the intratumoral abundance of anti-tumour T cells. The DDR1 extracellular domain (DDR1-ECD), but not its intracellular kinase domain, is required for immune exclusion. Membrane-untethered DDR1-ECD is sufficient to rescue the growth of
Ddr1
-knockout tumours in immunocompetent hosts. Mechanistically, the binding of DDR1-ECD to collagen enforces aligned collagen fibres and obstructs immune infiltration. ECD-neutralizing antibodies disrupt collagen fibre alignment, mitigate immune exclusion and inhibit tumour growth in immunocompetent hosts. Together, our findings identify a mechanism for immune exclusion and suggest an immunotherapeutic target for increasing immune accessibility through reconfiguration of the tumour ECM.
In mouse models of triple-negative breast cancer, the extracellular domain of the collagen receptor DDR1 has a role in tumour defence against the immune system, by aligning collagen fibres to obstruct immune infiltration.</description><subject>13/1</subject><subject>13/106</subject><subject>13/109</subject><subject>13/31</subject><subject>13/44</subject><subject>13/51</subject><subject>14</subject><subject>14/19</subject><subject>14/63</subject><subject>38</subject><subject>38/39</subject><subject>38/70</subject><subject>38/77</subject><subject>38/90</subject><subject>42</subject><subject>42/41</subject><subject>45</subject><subject>59</subject><subject>631/67/1347</subject><subject>631/67/327</subject><subject>64</subject><subject>64/60</subject><subject>82</subject><subject>82/29</subject><subject>82/51</subject><subject>82/80</subject><subject>82/83</subject><subject>96</subject><subject>96/21</subject><subject>96/31</subject><subject>96/95</subject><subject>Ablation</subject><subject>Alignment</subject><subject>Animal models</subject><subject>Animals</subject><subject>Antibodies</subject><subject>Breast cancer</subject><subject>Cell Line, Tumor</subject><subject>Collagen</subject><subject>Collagen - metabolism</subject><subject>Discoidin Domain Receptor 1 - antagonists & inhibitors</subject><subject>Discoidin Domain Receptor 1 - deficiency</subject><subject>Discoidin Domain Receptor 1 - genetics</subject><subject>Discoidin Domain Receptor 1 - metabolism</subject><subject>Disease Models, Animal</subject><subject>Domains</subject><subject>Extracellular matrix</subject><subject>Extracellular Matrix - immunology</subject><subject>Extracellular Matrix - metabolism</subject><subject>Female</subject><subject>Fibers</subject><subject>Gene Deletion</subject><subject>Gene expression</subject><subject>Gene Knockout Techniques</subject><subject>Genetic aspects</subject><subject>Health aspects</subject><subject>Humanities and Social Sciences</subject><subject>Humans</subject><subject>Immune response</subject><subject>Immunocompetence</subject><subject>Immunocompetence - immunology</subject><subject>Immunotherapy</subject><subject>Kinases</subject><subject>Lymphocytes</subject><subject>Lymphocytes T</subject><subject>Metastases</subject><subject>Mice</subject><subject>multidisciplinary</subject><subject>Physiological aspects</subject><subject>Protein-tyrosine kinase</subject><subject>Receptors</subject><subject>Reconfiguration</subject><subject>Science</subject><subject>Science (multidisciplinary)</subject><subject>Signal transduction</subject><subject>T-Lymphocytes - cytology</subject><subject>T-Lymphocytes - immunology</subject><subject>Triple Negative Breast Neoplasms - immunology</subject><subject>Triple Negative Breast Neoplasms - metabolism</subject><subject>Triple Negative Breast Neoplasms - therapy</subject><subject>Tumor Escape</subject><subject>Tumors</subject><subject>Tyrosine</subject><issn>0028-0836</issn><issn>1476-4687</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNp9kk1v1DAQhi0EomXhD3BAEVzgkOJvOxekquWjohJSKWfLcSbBVWJv7QSVf4_LlrKLVsiHkTzPvJ4Zvwg9J_iIYKbfZk6EljWmpMYcC1XTB-iQcCVrLrV6iA4xprrGmskD9CTnK4yxIIo_RgeMK0Z1Iw7R58tlikuqTk8vSLVOcYoz5MrFcbQDhKr3bYLKjn4IE4S5mmPlQ579YGeo_DQtASq4ceOSfQxP0aPejhme3cUV-vbh_eXJp_r8y8ezk-Pz2kmO51rJTvSaWGJBKdpJRjtQDXWNIK3iHWutFlo3tmuZpty6nkJLrCijAvSd5GyF3m1010s7QedKY8mOZp38ZNNPE603u5ngv5sh_jBas4bwpgi8vhNI8XqBPJvJZwdl5gBxyYaKholGEyEK-uof9KqsK5TxDJWYUYEl26IGO4LxoY_lXXcrao6lZooyUsIK1XuosmYoTcYAvS_XO_zLPbxb-2uzDR3tgcrpYPJur-qbnYLCzHAzD3bJ2Zx9vdhl6YZ1KeacoL9fMsHm1oNm40FTPGh-e9DQUvRi-3vuS_6YrgBsA-SSCgOkvzv9j-wvtUrkHQ</recordid><startdate>20211125</startdate><enddate>20211125</enddate><creator>Sun, 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DDR1 promotes collagen fibre alignment to instigate immune exclusion</title><author>Sun, Xiujie ; Wu, Bogang ; Chiang, Huai-Chin ; Deng, Hui ; Zhang, Xiaowen ; Xiong, Wei ; Liu, Junquan ; Rozeboom, Aaron M. ; Harris, Brent T. ; Blommaert, Eline ; Gomez, Antonio ; Garcia, Roderic Espin ; Zhou, Yufan ; Mitra, Payal ; Prevost, Madeleine ; Zhang, Deyi ; Banik, Debarati ; Isaacs, Claudine ; Berry, Deborah ; Lai, Catherine ; Chaldekas, Krysta ; Latham, Patricia S. ; Brantner, Christine A. ; Popratiloff, Anastas ; Jin, Victor X. ; Zhang, Ningyan ; Hu, Yanfen ; Pujana, Miguel Angel ; Curiel, Tyler J. ; An, Zhiqiang ; Li, Rong</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c640t-76d5f81a1ae772d632de792c951b74d3ba85889adb3824acf2eb1a5586eefd643</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>13/1</topic><topic>13/106</topic><topic>13/109</topic><topic>13/31</topic><topic>13/44</topic><topic>13/51</topic><topic>14</topic><topic>14/19</topic><topic>14/63</topic><topic>38</topic><topic>38/39</topic><topic>38/70</topic><topic>38/77</topic><topic>38/90</topic><topic>42</topic><topic>42/41</topic><topic>45</topic><topic>59</topic><topic>631/67/1347</topic><topic>631/67/327</topic><topic>64</topic><topic>64/60</topic><topic>82</topic><topic>82/29</topic><topic>82/51</topic><topic>82/80</topic><topic>82/83</topic><topic>96</topic><topic>96/21</topic><topic>96/31</topic><topic>96/95</topic><topic>Ablation</topic><topic>Alignment</topic><topic>Animal models</topic><topic>Animals</topic><topic>Antibodies</topic><topic>Breast cancer</topic><topic>Cell Line, Tumor</topic><topic>Collagen</topic><topic>Collagen - metabolism</topic><topic>Discoidin Domain Receptor 1 - antagonists & inhibitors</topic><topic>Discoidin Domain Receptor 1 - deficiency</topic><topic>Discoidin Domain Receptor 1 - genetics</topic><topic>Discoidin Domain Receptor 1 - metabolism</topic><topic>Disease Models, Animal</topic><topic>Domains</topic><topic>Extracellular matrix</topic><topic>Extracellular Matrix - immunology</topic><topic>Extracellular Matrix - metabolism</topic><topic>Female</topic><topic>Fibers</topic><topic>Gene Deletion</topic><topic>Gene expression</topic><topic>Gene Knockout Techniques</topic><topic>Genetic aspects</topic><topic>Health aspects</topic><topic>Humanities and Social Sciences</topic><topic>Humans</topic><topic>Immune response</topic><topic>Immunocompetence</topic><topic>Immunocompetence - immunology</topic><topic>Immunotherapy</topic><topic>Kinases</topic><topic>Lymphocytes</topic><topic>Lymphocytes T</topic><topic>Metastases</topic><topic>Mice</topic><topic>multidisciplinary</topic><topic>Physiological aspects</topic><topic>Protein-tyrosine kinase</topic><topic>Receptors</topic><topic>Reconfiguration</topic><topic>Science</topic><topic>Science (multidisciplinary)</topic><topic>Signal transduction</topic><topic>T-Lymphocytes - cytology</topic><topic>T-Lymphocytes - immunology</topic><topic>Triple Negative Breast Neoplasms - immunology</topic><topic>Triple Negative Breast Neoplasms - metabolism</topic><topic>Triple Negative Breast Neoplasms - therapy</topic><topic>Tumor Escape</topic><topic>Tumors</topic><topic>Tyrosine</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sun, Xiujie</creatorcontrib><creatorcontrib>Wu, Bogang</creatorcontrib><creatorcontrib>Chiang, Huai-Chin</creatorcontrib><creatorcontrib>Deng, Hui</creatorcontrib><creatorcontrib>Zhang, Xiaowen</creatorcontrib><creatorcontrib>Xiong, Wei</creatorcontrib><creatorcontrib>Liu, Junquan</creatorcontrib><creatorcontrib>Rozeboom, Aaron M.</creatorcontrib><creatorcontrib>Harris, Brent T.</creatorcontrib><creatorcontrib>Blommaert, Eline</creatorcontrib><creatorcontrib>Gomez, Antonio</creatorcontrib><creatorcontrib>Garcia, Roderic Espin</creatorcontrib><creatorcontrib>Zhou, Yufan</creatorcontrib><creatorcontrib>Mitra, Payal</creatorcontrib><creatorcontrib>Prevost, Madeleine</creatorcontrib><creatorcontrib>Zhang, Deyi</creatorcontrib><creatorcontrib>Banik, Debarati</creatorcontrib><creatorcontrib>Isaacs, Claudine</creatorcontrib><creatorcontrib>Berry, Deborah</creatorcontrib><creatorcontrib>Lai, Catherine</creatorcontrib><creatorcontrib>Chaldekas, Krysta</creatorcontrib><creatorcontrib>Latham, Patricia S.</creatorcontrib><creatorcontrib>Brantner, Christine A.</creatorcontrib><creatorcontrib>Popratiloff, Anastas</creatorcontrib><creatorcontrib>Jin, Victor X.</creatorcontrib><creatorcontrib>Zhang, Ningyan</creatorcontrib><creatorcontrib>Hu, Yanfen</creatorcontrib><creatorcontrib>Pujana, Miguel Angel</creatorcontrib><creatorcontrib>Curiel, Tyler J.</creatorcontrib><creatorcontrib>An, Zhiqiang</creatorcontrib><creatorcontrib>Li, Rong</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>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full 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Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sun, Xiujie</au><au>Wu, Bogang</au><au>Chiang, Huai-Chin</au><au>Deng, Hui</au><au>Zhang, Xiaowen</au><au>Xiong, Wei</au><au>Liu, Junquan</au><au>Rozeboom, Aaron M.</au><au>Harris, Brent T.</au><au>Blommaert, Eline</au><au>Gomez, Antonio</au><au>Garcia, Roderic Espin</au><au>Zhou, Yufan</au><au>Mitra, Payal</au><au>Prevost, Madeleine</au><au>Zhang, Deyi</au><au>Banik, Debarati</au><au>Isaacs, Claudine</au><au>Berry, Deborah</au><au>Lai, Catherine</au><au>Chaldekas, Krysta</au><au>Latham, Patricia S.</au><au>Brantner, Christine A.</au><au>Popratiloff, Anastas</au><au>Jin, Victor X.</au><au>Zhang, Ningyan</au><au>Hu, Yanfen</au><au>Pujana, Miguel Angel</au><au>Curiel, Tyler J.</au><au>An, Zhiqiang</au><au>Li, Rong</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Tumour DDR1 promotes collagen fibre alignment to instigate immune exclusion</atitle><jtitle>Nature (London)</jtitle><stitle>Nature</stitle><addtitle>Nature</addtitle><date>2021-11-25</date><risdate>2021</risdate><volume>599</volume><issue>7886</issue><spage>673</spage><epage>678</epage><pages>673-678</pages><issn>0028-0836</issn><eissn>1476-4687</eissn><abstract>Immune exclusion predicts poor patient outcomes in multiple malignancies, including triple-negative breast cancer (TNBC)
1
. The extracellular matrix (ECM) contributes to immune exclusion
2
. However, strategies to reduce ECM abundance are largely ineffective or generate undesired outcomes
3
,
4
. Here we show that discoidin domain receptor 1 (DDR1), a collagen receptor with tyrosine kinase activity
5
, instigates immune exclusion by promoting collagen fibre alignment. Ablation of
Ddr1
in tumours promotes the intratumoral penetration of T cells and obliterates tumour growth in mouse models of TNBC. Supporting this finding, in human TNBC the expression of DDR1 negatively correlates with the intratumoral abundance of anti-tumour T cells. The DDR1 extracellular domain (DDR1-ECD), but not its intracellular kinase domain, is required for immune exclusion. Membrane-untethered DDR1-ECD is sufficient to rescue the growth of
Ddr1
-knockout tumours in immunocompetent hosts. Mechanistically, the binding of DDR1-ECD to collagen enforces aligned collagen fibres and obstructs immune infiltration. ECD-neutralizing antibodies disrupt collagen fibre alignment, mitigate immune exclusion and inhibit tumour growth in immunocompetent hosts. Together, our findings identify a mechanism for immune exclusion and suggest an immunotherapeutic target for increasing immune accessibility through reconfiguration of the tumour ECM.
In mouse models of triple-negative breast cancer, the extracellular domain of the collagen receptor DDR1 has a role in tumour defence against the immune system, by aligning collagen fibres to obstruct immune infiltration.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>34732895</pmid><doi>10.1038/s41586-021-04057-2</doi><tpages>6</tpages><orcidid>https://orcid.org/0000-0002-8765-3471</orcidid><orcidid>https://orcid.org/0000-0001-6962-9411</orcidid><orcidid>https://orcid.org/0000-0003-2782-9444</orcidid><orcidid>https://orcid.org/0000-0003-3222-4044</orcidid><orcidid>https://orcid.org/0000-0003-0040-5158</orcidid><orcidid>https://orcid.org/0000-0002-7616-3362</orcidid><orcidid>https://orcid.org/0000-0002-4348-2180</orcidid><orcidid>https://orcid.org/0000-0001-5308-981X</orcidid><orcidid>https://orcid.org/0000-0003-2494-0964</orcidid><orcidid>https://orcid.org/0000-0002-8385-433X</orcidid><orcidid>https://orcid.org/0000-0001-9309-2335</orcidid><orcidid>https://orcid.org/0000-0003-1654-198X</orcidid><orcidid>https://orcid.org/0000-0002-6471-6580</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0028-0836 |
| ispartof | Nature (London), 2021-11, Vol.599 (7886), p.673-678 |
| issn | 0028-0836 1476-4687 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8839149 |
| source | MEDLINE; Nature Journals Online; SpringerLink Journals - AutoHoldings |
| subjects | 13/1 13/106 13/109 13/31 13/44 13/51 14 14/19 14/63 38 38/39 38/70 38/77 38/90 42 42/41 45 59 631/67/1347 631/67/327 64 64/60 82 82/29 82/51 82/80 82/83 96 96/21 96/31 96/95 Ablation Alignment Animal models Animals Antibodies Breast cancer Cell Line, Tumor Collagen Collagen - metabolism Discoidin Domain Receptor 1 - antagonists & inhibitors Discoidin Domain Receptor 1 - deficiency Discoidin Domain Receptor 1 - genetics Discoidin Domain Receptor 1 - metabolism Disease Models, Animal Domains Extracellular matrix Extracellular Matrix - immunology Extracellular Matrix - metabolism Female Fibers Gene Deletion Gene expression Gene Knockout Techniques Genetic aspects Health aspects Humanities and Social Sciences Humans Immune response Immunocompetence Immunocompetence - immunology Immunotherapy Kinases Lymphocytes Lymphocytes T Metastases Mice multidisciplinary Physiological aspects Protein-tyrosine kinase Receptors Reconfiguration Science Science (multidisciplinary) Signal transduction T-Lymphocytes - cytology T-Lymphocytes - immunology Triple Negative Breast Neoplasms - immunology Triple Negative Breast Neoplasms - metabolism Triple Negative Breast Neoplasms - therapy Tumor Escape Tumors Tyrosine |
| title | Tumour DDR1 promotes collagen fibre alignment to instigate immune exclusion |
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