Spatially organized multicellular immune hubs in human colorectal cancer
Immune responses to cancer are highly variable, with mismatch repair-deficient (MMRd) tumors exhibiting more anti-tumor immunity than mismatch repair-proficient (MMRp) tumors. To understand the rules governing these varied responses, we transcriptionally profiled 371,223 cells from colorectal tumors...
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| Veröffentlicht in: | Cell 2021-09, Vol.184 (18), p.4734-4752.e20 |
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| creator | Pelka, Karin Hofree, Matan Chen, Jonathan H. Sarkizova, Siranush Pirl, Joshua D. Jorgji, Vjola Bejnood, Alborz Dionne, Danielle Ge, William H. Xu, Katherine H. Chao, Sherry X. Zollinger, Daniel R. Lieb, David J. Reeves, Jason W. Fuhrman, Christopher A. Hoang, Margaret L. Delorey, Toni Nguyen, Lan T. Waldman, Julia Klapholz, Max Wakiro, Isaac Cohen, Ofir Albers, Julian Smillie, Christopher S. Cuoco, Michael S. Wu, Jingyi Su, Mei-ju Yeung, Jason Vijaykumar, Brinda Magnuson, Angela M. Asinovski, Natasha Moll, Tabea Goder-Reiser, Max N. Applebaum, Anise S. Brais, Lauren K. DelloStritto, Laura K. Denning, Sarah L. Phillips, Susannah T. Hill, Emma K. Meehan, Julia K. Frederick, Dennie T. Sharova, Tatyana Kanodia, Abhay Todres, Ellen Z. Jané-Valbuena, Judit Biton, Moshe Izar, Benjamin Lambden, Conner D. Clancy, Thomas E. Bleday, Ronald Melnitchouk, Nelya Irani, Jennifer Kunitake, Hiroko Berger, David L. Srivastava, Amitabh Hornick, Jason L. Ogino, Shuji Rotem, Asaf Vigneau, Sébastien Johnson, Bruce E. Corcoran, Ryan B. Sharpe, Arlene H. Kuchroo, Vijay K. Ng, Kimmie Giannakis, Marios Nieman, Linda T. Boland, Genevieve M. Aguirre, Andrew J. Anderson, Ana C. Rozenblatt-Rosen, Orit Regev, Aviv Hacohen, Nir |
| description | Immune responses to cancer are highly variable, with mismatch repair-deficient (MMRd) tumors exhibiting more anti-tumor immunity than mismatch repair-proficient (MMRp) tumors. To understand the rules governing these varied responses, we transcriptionally profiled 371,223 cells from colorectal tumors and adjacent normal tissues of 28 MMRp and 34 MMRd individuals. Analysis of 88 cell subsets and their 204 associated gene expression programs revealed extensive transcriptional and spatial remodeling across tumors. To discover hubs of interacting malignant and immune cells, we identified expression programs in different cell types that co-varied across tumors from affected individuals and used spatial profiling to localize coordinated programs. We discovered a myeloid cell-attracting hub at the tumor-luminal interface associated with tissue damage and an MMRd-enriched immune hub within the tumor, with activated T cells together with malignant and myeloid cells expressing T cell-attracting chemokines. By identifying interacting cellular programs, we reveal the logic underlying spatially organized immune-malignant cell networks.
[Display omitted]
•A scRNA-seq study reveals shared and distinct features of human MMRd and MMRp CRC•Co-variation of single-cell transcriptional programs across specimens predicts immune hubs•A myeloid-rich inflammatory hub is identified below the colonic lumen in human CRC•CXCR3-ligand+ cells form foci with activated T cells in human MMRd CRC
Single-cell transcriptomics-based co-variation analysis of human colorectal cancer identifies a spatially resolved myeloid-rich inflammatory hub that is shared by mismatch repair-deficient (MMRd) and mismatch repair-proficient (MMRp) tumors and CXCR3-ligand+ multicellular foci distinct for MMRd tumors. |
| doi_str_mv | 10.1016/j.cell.2021.08.003 |
| format | Article |
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To understand the rules governing these varied responses, we transcriptionally profiled 371,223 cells from colorectal tumors and adjacent normal tissues of 28 MMRp and 34 MMRd individuals. Analysis of 88 cell subsets and their 204 associated gene expression programs revealed extensive transcriptional and spatial remodeling across tumors. To discover hubs of interacting malignant and immune cells, we identified expression programs in different cell types that co-varied across tumors from affected individuals and used spatial profiling to localize coordinated programs. We discovered a myeloid cell-attracting hub at the tumor-luminal interface associated with tissue damage and an MMRd-enriched immune hub within the tumor, with activated T cells together with malignant and myeloid cells expressing T cell-attracting chemokines. By identifying interacting cellular programs, we reveal the logic underlying spatially organized immune-malignant cell networks.
[Display omitted]
•A scRNA-seq study reveals shared and distinct features of human MMRd and MMRp CRC•Co-variation of single-cell transcriptional programs across specimens predicts immune hubs•A myeloid-rich inflammatory hub is identified below the colonic lumen in human CRC•CXCR3-ligand+ cells form foci with activated T cells in human MMRd CRC
Single-cell transcriptomics-based co-variation analysis of human colorectal cancer identifies a spatially resolved myeloid-rich inflammatory hub that is shared by mismatch repair-deficient (MMRd) and mismatch repair-proficient (MMRp) tumors and CXCR3-ligand+ multicellular foci distinct for MMRd tumors.</description><identifier>ISSN: 0092-8674</identifier><identifier>EISSN: 1097-4172</identifier><identifier>DOI: 10.1016/j.cell.2021.08.003</identifier><identifier>PMID: 34450029</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>anti-tumor immunity ; Bone Morphogenetic Proteins - metabolism ; Cancer-Associated Fibroblasts - metabolism ; Cancer-Associated Fibroblasts - pathology ; Cell Compartmentation ; Cell Line, Tumor ; cell-cell interactions ; Chemokines - metabolism ; Cohort Studies ; colorectal cancer ; Colorectal Neoplasms - genetics ; Colorectal Neoplasms - immunology ; Colorectal Neoplasms - pathology ; DNA Mismatch Repair - genetics ; Endothelial Cells - metabolism ; Gene Expression Regulation, Neoplastic ; Humans ; Immunity ; Inflammation - pathology ; mismatch repair-deficient ; mismatch repair-proficient ; Monocytes - pathology ; MSI ; MSS ; Myeloid Cells - pathology ; Neutrophils - pathology ; scRNA-seq ; spatial ; Stromal Cells - metabolism ; T-Lymphocytes - metabolism ; Transcription, Genetic ; tumor atlas</subject><ispartof>Cell, 2021-09, Vol.184 (18), p.4734-4752.e20</ispartof><rights>2021 The Authors</rights><rights>Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c521t-a65503cad2a51270f311297daff1cfa7e13e7b2c64d54d567b7fa2fa951cf1a33</citedby><cites>FETCH-LOGICAL-c521t-a65503cad2a51270f311297daff1cfa7e13e7b2c64d54d567b7fa2fa951cf1a33</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0092867421009454$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,3537,27901,27902,65534</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34450029$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Pelka, Karin</creatorcontrib><creatorcontrib>Hofree, Matan</creatorcontrib><creatorcontrib>Chen, Jonathan H.</creatorcontrib><creatorcontrib>Sarkizova, Siranush</creatorcontrib><creatorcontrib>Pirl, Joshua D.</creatorcontrib><creatorcontrib>Jorgji, Vjola</creatorcontrib><creatorcontrib>Bejnood, Alborz</creatorcontrib><creatorcontrib>Dionne, Danielle</creatorcontrib><creatorcontrib>Ge, William H.</creatorcontrib><creatorcontrib>Xu, Katherine H.</creatorcontrib><creatorcontrib>Chao, Sherry X.</creatorcontrib><creatorcontrib>Zollinger, Daniel R.</creatorcontrib><creatorcontrib>Lieb, David J.</creatorcontrib><creatorcontrib>Reeves, Jason W.</creatorcontrib><creatorcontrib>Fuhrman, Christopher A.</creatorcontrib><creatorcontrib>Hoang, Margaret L.</creatorcontrib><creatorcontrib>Delorey, Toni</creatorcontrib><creatorcontrib>Nguyen, Lan T.</creatorcontrib><creatorcontrib>Waldman, Julia</creatorcontrib><creatorcontrib>Klapholz, Max</creatorcontrib><creatorcontrib>Wakiro, Isaac</creatorcontrib><creatorcontrib>Cohen, Ofir</creatorcontrib><creatorcontrib>Albers, Julian</creatorcontrib><creatorcontrib>Smillie, Christopher S.</creatorcontrib><creatorcontrib>Cuoco, Michael S.</creatorcontrib><creatorcontrib>Wu, Jingyi</creatorcontrib><creatorcontrib>Su, Mei-ju</creatorcontrib><creatorcontrib>Yeung, Jason</creatorcontrib><creatorcontrib>Vijaykumar, Brinda</creatorcontrib><creatorcontrib>Magnuson, Angela M.</creatorcontrib><creatorcontrib>Asinovski, Natasha</creatorcontrib><creatorcontrib>Moll, Tabea</creatorcontrib><creatorcontrib>Goder-Reiser, Max N.</creatorcontrib><creatorcontrib>Applebaum, Anise S.</creatorcontrib><creatorcontrib>Brais, Lauren K.</creatorcontrib><creatorcontrib>DelloStritto, Laura K.</creatorcontrib><creatorcontrib>Denning, Sarah L.</creatorcontrib><creatorcontrib>Phillips, Susannah T.</creatorcontrib><creatorcontrib>Hill, Emma K.</creatorcontrib><creatorcontrib>Meehan, Julia K.</creatorcontrib><creatorcontrib>Frederick, Dennie T.</creatorcontrib><creatorcontrib>Sharova, Tatyana</creatorcontrib><creatorcontrib>Kanodia, Abhay</creatorcontrib><creatorcontrib>Todres, Ellen Z.</creatorcontrib><creatorcontrib>Jané-Valbuena, Judit</creatorcontrib><creatorcontrib>Biton, Moshe</creatorcontrib><creatorcontrib>Izar, Benjamin</creatorcontrib><creatorcontrib>Lambden, Conner D.</creatorcontrib><creatorcontrib>Clancy, Thomas E.</creatorcontrib><creatorcontrib>Bleday, Ronald</creatorcontrib><creatorcontrib>Melnitchouk, Nelya</creatorcontrib><creatorcontrib>Irani, Jennifer</creatorcontrib><creatorcontrib>Kunitake, Hiroko</creatorcontrib><creatorcontrib>Berger, David L.</creatorcontrib><creatorcontrib>Srivastava, Amitabh</creatorcontrib><creatorcontrib>Hornick, Jason L.</creatorcontrib><creatorcontrib>Ogino, Shuji</creatorcontrib><creatorcontrib>Rotem, Asaf</creatorcontrib><creatorcontrib>Vigneau, Sébastien</creatorcontrib><creatorcontrib>Johnson, Bruce E.</creatorcontrib><creatorcontrib>Corcoran, Ryan B.</creatorcontrib><creatorcontrib>Sharpe, Arlene H.</creatorcontrib><creatorcontrib>Kuchroo, Vijay K.</creatorcontrib><creatorcontrib>Ng, Kimmie</creatorcontrib><creatorcontrib>Giannakis, Marios</creatorcontrib><creatorcontrib>Nieman, Linda T.</creatorcontrib><creatorcontrib>Boland, Genevieve M.</creatorcontrib><creatorcontrib>Aguirre, Andrew J.</creatorcontrib><creatorcontrib>Anderson, Ana C.</creatorcontrib><creatorcontrib>Rozenblatt-Rosen, Orit</creatorcontrib><creatorcontrib>Regev, Aviv</creatorcontrib><creatorcontrib>Hacohen, Nir</creatorcontrib><title>Spatially organized multicellular immune hubs in human colorectal cancer</title><title>Cell</title><addtitle>Cell</addtitle><description>Immune responses to cancer are highly variable, with mismatch repair-deficient (MMRd) tumors exhibiting more anti-tumor immunity than mismatch repair-proficient (MMRp) tumors. To understand the rules governing these varied responses, we transcriptionally profiled 371,223 cells from colorectal tumors and adjacent normal tissues of 28 MMRp and 34 MMRd individuals. Analysis of 88 cell subsets and their 204 associated gene expression programs revealed extensive transcriptional and spatial remodeling across tumors. To discover hubs of interacting malignant and immune cells, we identified expression programs in different cell types that co-varied across tumors from affected individuals and used spatial profiling to localize coordinated programs. We discovered a myeloid cell-attracting hub at the tumor-luminal interface associated with tissue damage and an MMRd-enriched immune hub within the tumor, with activated T cells together with malignant and myeloid cells expressing T cell-attracting chemokines. By identifying interacting cellular programs, we reveal the logic underlying spatially organized immune-malignant cell networks.
[Display omitted]
•A scRNA-seq study reveals shared and distinct features of human MMRd and MMRp CRC•Co-variation of single-cell transcriptional programs across specimens predicts immune hubs•A myeloid-rich inflammatory hub is identified below the colonic lumen in human CRC•CXCR3-ligand+ cells form foci with activated T cells in human MMRd CRC
Single-cell transcriptomics-based co-variation analysis of human colorectal cancer identifies a spatially resolved myeloid-rich inflammatory hub that is shared by mismatch repair-deficient (MMRd) and mismatch repair-proficient (MMRp) tumors and CXCR3-ligand+ multicellular foci distinct for MMRd tumors.</description><subject>anti-tumor immunity</subject><subject>Bone Morphogenetic Proteins - metabolism</subject><subject>Cancer-Associated Fibroblasts - metabolism</subject><subject>Cancer-Associated Fibroblasts - pathology</subject><subject>Cell Compartmentation</subject><subject>Cell Line, Tumor</subject><subject>cell-cell interactions</subject><subject>Chemokines - metabolism</subject><subject>Cohort Studies</subject><subject>colorectal cancer</subject><subject>Colorectal Neoplasms - genetics</subject><subject>Colorectal Neoplasms - immunology</subject><subject>Colorectal Neoplasms - pathology</subject><subject>DNA Mismatch Repair - genetics</subject><subject>Endothelial Cells - metabolism</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Humans</subject><subject>Immunity</subject><subject>Inflammation - pathology</subject><subject>mismatch repair-deficient</subject><subject>mismatch repair-proficient</subject><subject>Monocytes - pathology</subject><subject>MSI</subject><subject>MSS</subject><subject>Myeloid Cells - pathology</subject><subject>Neutrophils - pathology</subject><subject>scRNA-seq</subject><subject>spatial</subject><subject>Stromal Cells - metabolism</subject><subject>T-Lymphocytes - metabolism</subject><subject>Transcription, Genetic</subject><subject>tumor 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Christopher A. ; Hoang, Margaret L. ; Delorey, Toni ; Nguyen, Lan T. ; Waldman, Julia ; Klapholz, Max ; Wakiro, Isaac ; Cohen, Ofir ; Albers, Julian ; Smillie, Christopher S. ; Cuoco, Michael S. ; Wu, Jingyi ; Su, Mei-ju ; Yeung, Jason ; Vijaykumar, Brinda ; Magnuson, Angela M. ; Asinovski, Natasha ; Moll, Tabea ; Goder-Reiser, Max N. ; Applebaum, Anise S. ; Brais, Lauren K. ; DelloStritto, Laura K. ; Denning, Sarah L. ; Phillips, Susannah T. ; Hill, Emma K. ; Meehan, Julia K. ; Frederick, Dennie T. ; Sharova, Tatyana ; Kanodia, Abhay ; Todres, Ellen Z. ; Jané-Valbuena, Judit ; Biton, Moshe ; Izar, Benjamin ; Lambden, Conner D. ; Clancy, Thomas E. ; Bleday, Ronald ; Melnitchouk, Nelya ; Irani, Jennifer ; Kunitake, Hiroko ; Berger, David L. ; Srivastava, Amitabh ; Hornick, Jason L. ; Ogino, Shuji ; Rotem, Asaf ; Vigneau, Sébastien ; Johnson, Bruce E. ; Corcoran, Ryan B. ; Sharpe, Arlene H. ; Kuchroo, Vijay K. ; Ng, Kimmie ; Giannakis, Marios ; Nieman, Linda T. ; Boland, Genevieve M. ; Aguirre, Andrew J. ; Anderson, Ana C. ; Rozenblatt-Rosen, Orit ; Regev, Aviv ; Hacohen, Nir</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c521t-a65503cad2a51270f311297daff1cfa7e13e7b2c64d54d567b7fa2fa951cf1a33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>anti-tumor immunity</topic><topic>Bone Morphogenetic Proteins - metabolism</topic><topic>Cancer-Associated Fibroblasts - metabolism</topic><topic>Cancer-Associated Fibroblasts - pathology</topic><topic>Cell Compartmentation</topic><topic>Cell Line, Tumor</topic><topic>cell-cell interactions</topic><topic>Chemokines - metabolism</topic><topic>Cohort Studies</topic><topic>colorectal cancer</topic><topic>Colorectal Neoplasms - genetics</topic><topic>Colorectal Neoplasms - immunology</topic><topic>Colorectal Neoplasms - pathology</topic><topic>DNA Mismatch Repair - genetics</topic><topic>Endothelial Cells - metabolism</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Humans</topic><topic>Immunity</topic><topic>Inflammation - pathology</topic><topic>mismatch repair-deficient</topic><topic>mismatch repair-proficient</topic><topic>Monocytes - pathology</topic><topic>MSI</topic><topic>MSS</topic><topic>Myeloid Cells - pathology</topic><topic>Neutrophils - pathology</topic><topic>scRNA-seq</topic><topic>spatial</topic><topic>Stromal Cells - metabolism</topic><topic>T-Lymphocytes - metabolism</topic><topic>Transcription, Genetic</topic><topic>tumor atlas</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Pelka, Karin</creatorcontrib><creatorcontrib>Hofree, Matan</creatorcontrib><creatorcontrib>Chen, Jonathan H.</creatorcontrib><creatorcontrib>Sarkizova, Siranush</creatorcontrib><creatorcontrib>Pirl, Joshua D.</creatorcontrib><creatorcontrib>Jorgji, Vjola</creatorcontrib><creatorcontrib>Bejnood, Alborz</creatorcontrib><creatorcontrib>Dionne, Danielle</creatorcontrib><creatorcontrib>Ge, William H.</creatorcontrib><creatorcontrib>Xu, Katherine H.</creatorcontrib><creatorcontrib>Chao, Sherry X.</creatorcontrib><creatorcontrib>Zollinger, Daniel R.</creatorcontrib><creatorcontrib>Lieb, David J.</creatorcontrib><creatorcontrib>Reeves, Jason W.</creatorcontrib><creatorcontrib>Fuhrman, Christopher A.</creatorcontrib><creatorcontrib>Hoang, Margaret L.</creatorcontrib><creatorcontrib>Delorey, Toni</creatorcontrib><creatorcontrib>Nguyen, Lan T.</creatorcontrib><creatorcontrib>Waldman, Julia</creatorcontrib><creatorcontrib>Klapholz, Max</creatorcontrib><creatorcontrib>Wakiro, Isaac</creatorcontrib><creatorcontrib>Cohen, Ofir</creatorcontrib><creatorcontrib>Albers, Julian</creatorcontrib><creatorcontrib>Smillie, Christopher S.</creatorcontrib><creatorcontrib>Cuoco, Michael S.</creatorcontrib><creatorcontrib>Wu, Jingyi</creatorcontrib><creatorcontrib>Su, Mei-ju</creatorcontrib><creatorcontrib>Yeung, Jason</creatorcontrib><creatorcontrib>Vijaykumar, Brinda</creatorcontrib><creatorcontrib>Magnuson, Angela M.</creatorcontrib><creatorcontrib>Asinovski, Natasha</creatorcontrib><creatorcontrib>Moll, Tabea</creatorcontrib><creatorcontrib>Goder-Reiser, Max N.</creatorcontrib><creatorcontrib>Applebaum, Anise S.</creatorcontrib><creatorcontrib>Brais, Lauren K.</creatorcontrib><creatorcontrib>DelloStritto, Laura K.</creatorcontrib><creatorcontrib>Denning, Sarah L.</creatorcontrib><creatorcontrib>Phillips, Susannah T.</creatorcontrib><creatorcontrib>Hill, Emma K.</creatorcontrib><creatorcontrib>Meehan, Julia K.</creatorcontrib><creatorcontrib>Frederick, Dennie T.</creatorcontrib><creatorcontrib>Sharova, Tatyana</creatorcontrib><creatorcontrib>Kanodia, Abhay</creatorcontrib><creatorcontrib>Todres, Ellen Z.</creatorcontrib><creatorcontrib>Jané-Valbuena, Judit</creatorcontrib><creatorcontrib>Biton, Moshe</creatorcontrib><creatorcontrib>Izar, Benjamin</creatorcontrib><creatorcontrib>Lambden, Conner D.</creatorcontrib><creatorcontrib>Clancy, Thomas E.</creatorcontrib><creatorcontrib>Bleday, Ronald</creatorcontrib><creatorcontrib>Melnitchouk, Nelya</creatorcontrib><creatorcontrib>Irani, Jennifer</creatorcontrib><creatorcontrib>Kunitake, Hiroko</creatorcontrib><creatorcontrib>Berger, David L.</creatorcontrib><creatorcontrib>Srivastava, Amitabh</creatorcontrib><creatorcontrib>Hornick, Jason L.</creatorcontrib><creatorcontrib>Ogino, Shuji</creatorcontrib><creatorcontrib>Rotem, Asaf</creatorcontrib><creatorcontrib>Vigneau, Sébastien</creatorcontrib><creatorcontrib>Johnson, Bruce E.</creatorcontrib><creatorcontrib>Corcoran, Ryan B.</creatorcontrib><creatorcontrib>Sharpe, Arlene H.</creatorcontrib><creatorcontrib>Kuchroo, Vijay K.</creatorcontrib><creatorcontrib>Ng, Kimmie</creatorcontrib><creatorcontrib>Giannakis, Marios</creatorcontrib><creatorcontrib>Nieman, Linda T.</creatorcontrib><creatorcontrib>Boland, Genevieve M.</creatorcontrib><creatorcontrib>Aguirre, Andrew J.</creatorcontrib><creatorcontrib>Anderson, Ana C.</creatorcontrib><creatorcontrib>Rozenblatt-Rosen, Orit</creatorcontrib><creatorcontrib>Regev, Aviv</creatorcontrib><creatorcontrib>Hacohen, Nir</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect: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>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Pelka, Karin</au><au>Hofree, Matan</au><au>Chen, Jonathan H.</au><au>Sarkizova, Siranush</au><au>Pirl, Joshua D.</au><au>Jorgji, Vjola</au><au>Bejnood, Alborz</au><au>Dionne, Danielle</au><au>Ge, William H.</au><au>Xu, Katherine H.</au><au>Chao, Sherry X.</au><au>Zollinger, Daniel R.</au><au>Lieb, David J.</au><au>Reeves, Jason W.</au><au>Fuhrman, Christopher A.</au><au>Hoang, Margaret L.</au><au>Delorey, Toni</au><au>Nguyen, Lan T.</au><au>Waldman, Julia</au><au>Klapholz, Max</au><au>Wakiro, Isaac</au><au>Cohen, Ofir</au><au>Albers, Julian</au><au>Smillie, Christopher S.</au><au>Cuoco, Michael S.</au><au>Wu, Jingyi</au><au>Su, Mei-ju</au><au>Yeung, Jason</au><au>Vijaykumar, Brinda</au><au>Magnuson, Angela M.</au><au>Asinovski, Natasha</au><au>Moll, Tabea</au><au>Goder-Reiser, Max N.</au><au>Applebaum, Anise S.</au><au>Brais, Lauren K.</au><au>DelloStritto, Laura K.</au><au>Denning, Sarah L.</au><au>Phillips, Susannah T.</au><au>Hill, Emma K.</au><au>Meehan, Julia K.</au><au>Frederick, Dennie T.</au><au>Sharova, Tatyana</au><au>Kanodia, Abhay</au><au>Todres, Ellen Z.</au><au>Jané-Valbuena, Judit</au><au>Biton, Moshe</au><au>Izar, Benjamin</au><au>Lambden, Conner D.</au><au>Clancy, Thomas E.</au><au>Bleday, Ronald</au><au>Melnitchouk, Nelya</au><au>Irani, Jennifer</au><au>Kunitake, Hiroko</au><au>Berger, David L.</au><au>Srivastava, Amitabh</au><au>Hornick, Jason L.</au><au>Ogino, Shuji</au><au>Rotem, Asaf</au><au>Vigneau, Sébastien</au><au>Johnson, Bruce E.</au><au>Corcoran, Ryan B.</au><au>Sharpe, Arlene H.</au><au>Kuchroo, Vijay K.</au><au>Ng, Kimmie</au><au>Giannakis, Marios</au><au>Nieman, Linda T.</au><au>Boland, Genevieve M.</au><au>Aguirre, Andrew J.</au><au>Anderson, Ana C.</au><au>Rozenblatt-Rosen, Orit</au><au>Regev, Aviv</au><au>Hacohen, Nir</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Spatially organized multicellular immune hubs in human colorectal cancer</atitle><jtitle>Cell</jtitle><addtitle>Cell</addtitle><date>2021-09-02</date><risdate>2021</risdate><volume>184</volume><issue>18</issue><spage>4734</spage><epage>4752.e20</epage><pages>4734-4752.e20</pages><issn>0092-8674</issn><eissn>1097-4172</eissn><abstract>Immune responses to cancer are highly variable, with mismatch repair-deficient (MMRd) tumors exhibiting more anti-tumor immunity than mismatch repair-proficient (MMRp) tumors. To understand the rules governing these varied responses, we transcriptionally profiled 371,223 cells from colorectal tumors and adjacent normal tissues of 28 MMRp and 34 MMRd individuals. Analysis of 88 cell subsets and their 204 associated gene expression programs revealed extensive transcriptional and spatial remodeling across tumors. To discover hubs of interacting malignant and immune cells, we identified expression programs in different cell types that co-varied across tumors from affected individuals and used spatial profiling to localize coordinated programs. We discovered a myeloid cell-attracting hub at the tumor-luminal interface associated with tissue damage and an MMRd-enriched immune hub within the tumor, with activated T cells together with malignant and myeloid cells expressing T cell-attracting chemokines. By identifying interacting cellular programs, we reveal the logic underlying spatially organized immune-malignant cell networks.
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•A scRNA-seq study reveals shared and distinct features of human MMRd and MMRp CRC•Co-variation of single-cell transcriptional programs across specimens predicts immune hubs•A myeloid-rich inflammatory hub is identified below the colonic lumen in human CRC•CXCR3-ligand+ cells form foci with activated T cells in human MMRd CRC
Single-cell transcriptomics-based co-variation analysis of human colorectal cancer identifies a spatially resolved myeloid-rich inflammatory hub that is shared by mismatch repair-deficient (MMRd) and mismatch repair-proficient (MMRp) tumors and CXCR3-ligand+ multicellular foci distinct for MMRd tumors.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>34450029</pmid><doi>10.1016/j.cell.2021.08.003</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0092-8674 |
| ispartof | Cell, 2021-09, Vol.184 (18), p.4734-4752.e20 |
| issn | 0092-8674 1097-4172 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8772395 |
| source | MEDLINE; Cell Press Free Archives; Elsevier ScienceDirect Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | anti-tumor immunity Bone Morphogenetic Proteins - metabolism Cancer-Associated Fibroblasts - metabolism Cancer-Associated Fibroblasts - pathology Cell Compartmentation Cell Line, Tumor cell-cell interactions Chemokines - metabolism Cohort Studies colorectal cancer Colorectal Neoplasms - genetics Colorectal Neoplasms - immunology Colorectal Neoplasms - pathology DNA Mismatch Repair - genetics Endothelial Cells - metabolism Gene Expression Regulation, Neoplastic Humans Immunity Inflammation - pathology mismatch repair-deficient mismatch repair-proficient Monocytes - pathology MSI MSS Myeloid Cells - pathology Neutrophils - pathology scRNA-seq spatial Stromal Cells - metabolism T-Lymphocytes - metabolism Transcription, Genetic tumor atlas |
| title | Spatially organized multicellular immune hubs in human colorectal cancer |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-21T22%3A21%3A29IST&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=Spatially%20organized%20multicellular%20immune%20hubs%20in%20human%20colorectal%20cancer&rft.jtitle=Cell&rft.au=Pelka,%20Karin&rft.date=2021-09-02&rft.volume=184&rft.issue=18&rft.spage=4734&rft.epage=4752.e20&rft.pages=4734-4752.e20&rft.issn=0092-8674&rft.eissn=1097-4172&rft_id=info:doi/10.1016/j.cell.2021.08.003&rft_dat=%3Cproquest_pubme%3E2566039900%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=2566039900&rft_id=info:pmid/34450029&rft_els_id=S0092867421009454&rfr_iscdi=true |