Uncovering NK cell sabotage in gut diseases via single cell transcriptomics
The identification of immune environments and cellular interactions in the colon microenvironment is essential for understanding the mechanisms of chronic inflammatory disease. Despite occurring in the same organ, there is a significant gap in understanding the pathophysiology of ulcerative colitis...
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| Veröffentlicht in: | PLOS ONE 2025-01, Vol.20 (1), p.e0315981 |
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| creator | Lee, Hansong Ko, Dai Sik Heo, Hye Jin Baek, Seung Eun Kim, Eun Kyoung Kwon, Eun Jung Kang, Junho Yu, Yeuni Baryawno, Ninib Kim, Kihun Lee, Dongjun Kim, Yun Hak |
| description | The identification of immune environments and cellular interactions in the colon microenvironment is essential for understanding the mechanisms of chronic inflammatory disease. Despite occurring in the same organ, there is a significant gap in understanding the pathophysiology of ulcerative colitis (UC) and colorectal cancer (CRC). Our study aims to address the distinct immunopathological response of UC and CRC. Using single-cell RNA sequencing datasets, we analyzed the profiles of immune cells in colorectal tissues obtained from healthy donors, UC patients, and CRC patients. The colon tissues from patients and healthy participants were visualized by immunostaining followed by laser confocal microscopy for select targets. Natural killer (NK) cells from UC patients on medication showed reduced cytotoxicity compared to those from healthy individuals. Nonetheless, a UC-specific pathway called the BAG6-NCR3 axis led to higher levels of inflammatory cytokines and increased the cytotoxicity of NCR3+ NK cells, thereby contributing to the persistence of colitis. In the context of colorectal cancer (CRC), both NK cells and CD8+ T cells exhibited significant changes in cytotoxicity and exhaustion. The GALECTIN-9 (LGALS9)-HAVCR2 axis was identified as one of the CRC-specific pathways. Within this pathway, NK cells solely communicated with myeloid cells under CRC conditions. HAVCR2+ NK cells from CRC patients suppressed NK cell-mediated cytotoxicity, indicating a reduction in immune surveillance. Overall, we elucidated the comprehensive UC and CRC immune microenvironments and NK cell-mediated immune responses. Our findings can aid in selecting therapeutic targets that increase the efficacy of immunotherapy. |
| doi_str_mv | 10.1371/journal.pone.0315981 |
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Despite occurring in the same organ, there is a significant gap in understanding the pathophysiology of ulcerative colitis (UC) and colorectal cancer (CRC). Our study aims to address the distinct immunopathological response of UC and CRC. Using single-cell RNA sequencing datasets, we analyzed the profiles of immune cells in colorectal tissues obtained from healthy donors, UC patients, and CRC patients. The colon tissues from patients and healthy participants were visualized by immunostaining followed by laser confocal microscopy for select targets. Natural killer (NK) cells from UC patients on medication showed reduced cytotoxicity compared to those from healthy individuals. Nonetheless, a UC-specific pathway called the BAG6-NCR3 axis led to higher levels of inflammatory cytokines and increased the cytotoxicity of NCR3+ NK cells, thereby contributing to the persistence of colitis. In the context of colorectal cancer (CRC), both NK cells and CD8+ T cells exhibited significant changes in cytotoxicity and exhaustion. The GALECTIN-9 (LGALS9)-HAVCR2 axis was identified as one of the CRC-specific pathways. Within this pathway, NK cells solely communicated with myeloid cells under CRC conditions. HAVCR2+ NK cells from CRC patients suppressed NK cell-mediated cytotoxicity, indicating a reduction in immune surveillance. Overall, we elucidated the comprehensive UC and CRC immune microenvironments and NK cell-mediated immune responses. Our findings can aid in selecting therapeutic targets that increase the efficacy of immunotherapy.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0315981</identifier><identifier>PMID: 39752457</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Biopsy ; Cancer ; Cancer therapies ; CD8 antigen ; CD8-Positive T-Lymphocytes - immunology ; Cells ; Colitis, Ulcerative - genetics ; Colitis, Ulcerative - immunology ; Colitis, Ulcerative - pathology ; Colon ; Colon - immunology ; Colon - metabolism ; Colon - pathology ; Colorectal cancer ; Colorectal carcinoma ; Colorectal Neoplasms - genetics ; Colorectal Neoplasms - immunology ; Colorectal Neoplasms - pathology ; Communication ; Confocal microscopy ; Cytotoxicity ; Datasets ; Female ; Galectin-9 ; Galectins - genetics ; Galectins - metabolism ; Gene expression ; Gene sequencing ; Genetic aspects ; Genomics ; Health aspects ; Hepatitis A Virus Cellular Receptor 2 - genetics ; Hepatitis A Virus Cellular Receptor 2 - metabolism ; Humans ; Immune response ; Immune response (cell-mediated) ; Immune system ; Immunology ; Immunosurveillance ; Immunotherapy ; Inflammation ; Inflammatory bowel disease ; Inflammatory bowel diseases ; Killer cells ; Killer Cells, Natural - immunology ; Killer Cells, Natural - metabolism ; Ligands ; Lymphocytes ; Lymphocytes T ; Male ; Medical research ; Medicine, Experimental ; Microenvironments ; Middle Aged ; Myeloid cells ; Natural killer cells ; Pathophysiology ; Physiological aspects ; Rectum ; Sabotage ; Single-Cell Analysis ; Stomach diseases ; Therapeutic targets ; Toxicity ; Transcriptome ; Transcriptomics ; Ulcerative colitis</subject><ispartof>PLOS ONE, 2025-01, Vol.20 (1), p.e0315981</ispartof><rights>Copyright: © 2025 Lee et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</rights><rights>COPYRIGHT 2025 Public Library of Science</rights><rights>2025 Lee et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2025 Lee et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c4691-d9e152826639aadf86e167c27c95fdd94a286afb591425a08d75690217f8df4d3</cites><orcidid>0000-0002-9796-8266 ; 0000-0001-6828-401X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0315981&type=printable$$EPDF$$P50$$Gplos$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://journals.plos.org/plosone/article?id=10.1371/journal.pone.0315981$$EHTML$$P50$$Gplos$$Hfree_for_read</linktohtml><link.rule.ids>230,314,550,776,780,860,881,2096,2915,23845,27901,27902,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39752457$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttp://kipublications.ki.se/Default.aspx?queryparsed=id:239752457$$DView record from Swedish Publication Index$$Hfree_for_read</backlink></links><search><creatorcontrib>Lee, Hansong</creatorcontrib><creatorcontrib>Ko, Dai Sik</creatorcontrib><creatorcontrib>Heo, Hye Jin</creatorcontrib><creatorcontrib>Baek, Seung Eun</creatorcontrib><creatorcontrib>Kim, Eun Kyoung</creatorcontrib><creatorcontrib>Kwon, Eun Jung</creatorcontrib><creatorcontrib>Kang, Junho</creatorcontrib><creatorcontrib>Yu, Yeuni</creatorcontrib><creatorcontrib>Baryawno, Ninib</creatorcontrib><creatorcontrib>Kim, Kihun</creatorcontrib><creatorcontrib>Lee, Dongjun</creatorcontrib><creatorcontrib>Kim, Yun Hak</creatorcontrib><title>Uncovering NK cell sabotage in gut diseases via single cell transcriptomics</title><title>PLOS ONE</title><addtitle>PLoS One</addtitle><description>The identification of immune environments and cellular interactions in the colon microenvironment is essential for understanding the mechanisms of chronic inflammatory disease. Despite occurring in the same organ, there is a significant gap in understanding the pathophysiology of ulcerative colitis (UC) and colorectal cancer (CRC). Our study aims to address the distinct immunopathological response of UC and CRC. Using single-cell RNA sequencing datasets, we analyzed the profiles of immune cells in colorectal tissues obtained from healthy donors, UC patients, and CRC patients. The colon tissues from patients and healthy participants were visualized by immunostaining followed by laser confocal microscopy for select targets. Natural killer (NK) cells from UC patients on medication showed reduced cytotoxicity compared to those from healthy individuals. Nonetheless, a UC-specific pathway called the BAG6-NCR3 axis led to higher levels of inflammatory cytokines and increased the cytotoxicity of NCR3+ NK cells, thereby contributing to the persistence of colitis. In the context of colorectal cancer (CRC), both NK cells and CD8+ T cells exhibited significant changes in cytotoxicity and exhaustion. The GALECTIN-9 (LGALS9)-HAVCR2 axis was identified as one of the CRC-specific pathways. Within this pathway, NK cells solely communicated with myeloid cells under CRC conditions. HAVCR2+ NK cells from CRC patients suppressed NK cell-mediated cytotoxicity, indicating a reduction in immune surveillance. Overall, we elucidated the comprehensive UC and CRC immune microenvironments and NK cell-mediated immune responses. Our findings can aid in selecting therapeutic targets that increase the efficacy of immunotherapy.</description><subject>Biopsy</subject><subject>Cancer</subject><subject>Cancer therapies</subject><subject>CD8 antigen</subject><subject>CD8-Positive T-Lymphocytes - immunology</subject><subject>Cells</subject><subject>Colitis, Ulcerative - genetics</subject><subject>Colitis, Ulcerative - immunology</subject><subject>Colitis, Ulcerative - pathology</subject><subject>Colon</subject><subject>Colon - immunology</subject><subject>Colon - metabolism</subject><subject>Colon - pathology</subject><subject>Colorectal cancer</subject><subject>Colorectal carcinoma</subject><subject>Colorectal Neoplasms - genetics</subject><subject>Colorectal Neoplasms - immunology</subject><subject>Colorectal Neoplasms - pathology</subject><subject>Communication</subject><subject>Confocal microscopy</subject><subject>Cytotoxicity</subject><subject>Datasets</subject><subject>Female</subject><subject>Galectin-9</subject><subject>Galectins - genetics</subject><subject>Galectins - metabolism</subject><subject>Gene expression</subject><subject>Gene sequencing</subject><subject>Genetic aspects</subject><subject>Genomics</subject><subject>Health aspects</subject><subject>Hepatitis A Virus Cellular Receptor 2 - genetics</subject><subject>Hepatitis A Virus Cellular Receptor 2 - metabolism</subject><subject>Humans</subject><subject>Immune response</subject><subject>Immune response (cell-mediated)</subject><subject>Immune system</subject><subject>Immunology</subject><subject>Immunosurveillance</subject><subject>Immunotherapy</subject><subject>Inflammation</subject><subject>Inflammatory bowel disease</subject><subject>Inflammatory bowel diseases</subject><subject>Killer cells</subject><subject>Killer Cells, Natural - immunology</subject><subject>Killer Cells, Natural - metabolism</subject><subject>Ligands</subject><subject>Lymphocytes</subject><subject>Lymphocytes T</subject><subject>Male</subject><subject>Medical research</subject><subject>Medicine, Experimental</subject><subject>Microenvironments</subject><subject>Middle Aged</subject><subject>Myeloid cells</subject><subject>Natural killer cells</subject><subject>Pathophysiology</subject><subject>Physiological aspects</subject><subject>Rectum</subject><subject>Sabotage</subject><subject>Single-Cell Analysis</subject><subject>Stomach diseases</subject><subject>Therapeutic targets</subject><subject>Toxicity</subject><subject>Transcriptome</subject><subject>Transcriptomics</subject><subject>Ulcerative 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NK cell sabotage in gut diseases via single cell transcriptomics</title><author>Lee, Hansong ; Ko, Dai Sik ; Heo, Hye Jin ; Baek, Seung Eun ; Kim, Eun Kyoung ; Kwon, Eun Jung ; Kang, Junho ; Yu, Yeuni ; Baryawno, Ninib ; Kim, Kihun ; Lee, Dongjun ; Kim, Yun Hak</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4691-d9e152826639aadf86e167c27c95fdd94a286afb591425a08d75690217f8df4d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2025</creationdate><topic>Biopsy</topic><topic>Cancer</topic><topic>Cancer therapies</topic><topic>CD8 antigen</topic><topic>CD8-Positive T-Lymphocytes - immunology</topic><topic>Cells</topic><topic>Colitis, Ulcerative - genetics</topic><topic>Colitis, Ulcerative - immunology</topic><topic>Colitis, Ulcerative - pathology</topic><topic>Colon</topic><topic>Colon - immunology</topic><topic>Colon - metabolism</topic><topic>Colon - pathology</topic><topic>Colorectal 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Articles</collection><collection>SWEPUB Freely available online</collection><collection>SwePub Articles full text</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PLOS ONE</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lee, Hansong</au><au>Ko, Dai Sik</au><au>Heo, Hye Jin</au><au>Baek, Seung Eun</au><au>Kim, Eun Kyoung</au><au>Kwon, Eun Jung</au><au>Kang, Junho</au><au>Yu, Yeuni</au><au>Baryawno, Ninib</au><au>Kim, Kihun</au><au>Lee, Dongjun</au><au>Kim, Yun Hak</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Uncovering NK cell sabotage in gut diseases via single cell transcriptomics</atitle><jtitle>PLOS ONE</jtitle><addtitle>PLoS One</addtitle><date>2025-01-03</date><risdate>2025</risdate><volume>20</volume><issue>1</issue><spage>e0315981</spage><pages>e0315981-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>The identification of immune environments and cellular interactions in the colon microenvironment is essential for understanding the mechanisms of chronic inflammatory disease. Despite occurring in the same organ, there is a significant gap in understanding the pathophysiology of ulcerative colitis (UC) and colorectal cancer (CRC). Our study aims to address the distinct immunopathological response of UC and CRC. Using single-cell RNA sequencing datasets, we analyzed the profiles of immune cells in colorectal tissues obtained from healthy donors, UC patients, and CRC patients. The colon tissues from patients and healthy participants were visualized by immunostaining followed by laser confocal microscopy for select targets. Natural killer (NK) cells from UC patients on medication showed reduced cytotoxicity compared to those from healthy individuals. Nonetheless, a UC-specific pathway called the BAG6-NCR3 axis led to higher levels of inflammatory cytokines and increased the cytotoxicity of NCR3+ NK cells, thereby contributing to the persistence of colitis. In the context of colorectal cancer (CRC), both NK cells and CD8+ T cells exhibited significant changes in cytotoxicity and exhaustion. The GALECTIN-9 (LGALS9)-HAVCR2 axis was identified as one of the CRC-specific pathways. Within this pathway, NK cells solely communicated with myeloid cells under CRC conditions. HAVCR2+ NK cells from CRC patients suppressed NK cell-mediated cytotoxicity, indicating a reduction in immune surveillance. Overall, we elucidated the comprehensive UC and CRC immune microenvironments and NK cell-mediated immune responses. Our findings can aid in selecting therapeutic targets that increase the efficacy of immunotherapy.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>39752457</pmid><doi>10.1371/journal.pone.0315981</doi><tpages>e0315981</tpages><orcidid>https://orcid.org/0000-0002-9796-8266</orcidid><orcidid>https://orcid.org/0000-0001-6828-401X</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PLOS ONE, 2025-01, Vol.20 (1), p.e0315981 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_3151369536 |
| source | Public Library of Science (PLoS) Journals Open Access; MEDLINE; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central; SWEPUB Freely available online; Free Full-Text Journals in Chemistry |
| subjects | Biopsy Cancer Cancer therapies CD8 antigen CD8-Positive T-Lymphocytes - immunology Cells Colitis, Ulcerative - genetics Colitis, Ulcerative - immunology Colitis, Ulcerative - pathology Colon Colon - immunology Colon - metabolism Colon - pathology Colorectal cancer Colorectal carcinoma Colorectal Neoplasms - genetics Colorectal Neoplasms - immunology Colorectal Neoplasms - pathology Communication Confocal microscopy Cytotoxicity Datasets Female Galectin-9 Galectins - genetics Galectins - metabolism Gene expression Gene sequencing Genetic aspects Genomics Health aspects Hepatitis A Virus Cellular Receptor 2 - genetics Hepatitis A Virus Cellular Receptor 2 - metabolism Humans Immune response Immune response (cell-mediated) Immune system Immunology Immunosurveillance Immunotherapy Inflammation Inflammatory bowel disease Inflammatory bowel diseases Killer cells Killer Cells, Natural - immunology Killer Cells, Natural - metabolism Ligands Lymphocytes Lymphocytes T Male Medical research Medicine, Experimental Microenvironments Middle Aged Myeloid cells Natural killer cells Pathophysiology Physiological aspects Rectum Sabotage Single-Cell Analysis Stomach diseases Therapeutic targets Toxicity Transcriptome Transcriptomics Ulcerative colitis |
| title | Uncovering NK cell sabotage in gut diseases via single cell transcriptomics |
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