Single-cell RNA sequencing unveils the communications between malignant T and myeloid cells contributing to tumor growth and immunosuppression in cutaneous T-cell lymphoma
Cutaneous T cell lymphoma (CTCL) is characterized by the accumulation of malignant T cells in the skin. However, advanced CTCL pathophysiology remains elusive and therapeutic options are limited due to the high intratumoral heterogeneity and complicated tumor microenvironment (TME). By comparing the...
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Veröffentlicht in: | Cancer letters 2022-12, Vol.551, p.215972, Article 215972 |
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description | Cutaneous T cell lymphoma (CTCL) is characterized by the accumulation of malignant T cells in the skin. However, advanced CTCL pathophysiology remains elusive and therapeutic options are limited due to the high intratumoral heterogeneity and complicated tumor microenvironment (TME). By comparing the single-cell RNA-seq (scRNA-seq) data from advanced CTCL patients and healthy controls (HCs), we showed that CTCL had a higher enrichment of T/NK and myeloid cells. Subpopulations of T cells (CXCR3+, GNLY+, CREM+, and MKI67+ T cells), with high proliferation, stemness, and copy number variation (CNV) levels, contribute to the malignancy of CTCL. Besides, CCL13+ monocytes/macrophages and LAMP3+ cDC cells were enriched and mediated the immunosuppression via inhibitory interactions with malignant T cells, such as CD47-SIRPA, MIF-CD74, and CCR1-CCL18. Notably, elevated expressions of S100A9 and its receptor TLR4, as well as the activation of downstream toll-like receptor and NF-κB pathway were observed in both malignant cells and myeloid cells in CTCL. Cell co-culture experiments further confirmed that the interaction between malignant CTCL cells and macrophages contributed to tumor growth via S100A9 upregulation and NF-kb activation. Our results showed that blocking the S100A9-TLR4 interaction using tasquinimod could inactivate the NF-κB pathway and inhibit the growth of CTCL tumor cells, and trigger cell apoptosis. Collectively, our study revealed a landscape of immunosuppressive TME mediated by interactions between malignant T cells and myeloid cells, and provided novel targets and potential treatment strategies for advanced CTCL patients.
•CTCL has a higher enrichment of T and myeloid cells compared with healthy controls (HCs).•T cell subpopulations with high proliferation, stemness and CNV levels, contribute to the malignancy of CTCL.•CCL13+ mono/macrophages and LAMP3+ cDC cells interact with malignant T cells to shape the immunosuppression of CTCL.•NF-κB pathway induced by S100A9 and TLR4 interaction is activated in both malignant and myeloid cells in CTCL.•Blocking the S100A9-TLR4 interaction could inactivate the NF-κB pathway and inhibit the growth of CTCL tumor cells. |
doi_str_mv | 10.1016/j.canlet.2022.215972 |
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•CTCL has a higher enrichment of T and myeloid cells compared with healthy controls (HCs).•T cell subpopulations with high proliferation, stemness and CNV levels, contribute to the malignancy of CTCL.•CCL13+ mono/macrophages and LAMP3+ cDC cells interact with malignant T cells to shape the immunosuppression of CTCL.•NF-κB pathway induced by S100A9 and TLR4 interaction is activated in both malignant and myeloid cells in CTCL.•Blocking the S100A9-TLR4 interaction could inactivate the NF-κB pathway and inhibit the growth of CTCL tumor cells.</description><identifier>ISSN: 0304-3835</identifier><identifier>ISSN: 1872-7980</identifier><identifier>EISSN: 1872-7980</identifier><identifier>DOI: 10.1016/j.canlet.2022.215972</identifier><identifier>PMID: 36265653</identifier><language>eng</language><publisher>Ireland: Elsevier B.V</publisher><subject>Apoptosis ; CC chemokine receptors ; CCL18 protein ; CCR1 protein ; Cell culture ; Cell proliferation ; Copy number ; Cutaneous T cell lymphoma ; CXCR3 protein ; Cytotoxicity ; DNA Copy Number Variations ; Ecosystems ; Enzymes ; Humans ; Immunosuppression ; Immunosuppression Therapy ; Intratumoral heterogeneity ; Lymphocytes ; Lymphocytes T ; Lymphoma ; Lymphoma, T-Cell, Cutaneous - drug therapy ; Lymphoma, T-Cell, Cutaneous - genetics ; Lymphoma, T-Cell, Cutaneous - pathology ; Macrophages ; Malignancy ; Medical prognosis ; Monocytes ; Myeloid cells ; Myeloid Cells - metabolism ; NF-kappa B - genetics ; NF-κB protein ; Patients ; S100A9 ; Sequence Analysis, RNA ; Skin Neoplasms - pathology ; Statistical analysis ; T-cell lymphoma ; TLR4 protein ; Toll-Like Receptor 4 - genetics ; Toll-like receptors ; Tumor cells ; Tumor Microenvironment</subject><ispartof>Cancer letters, 2022-12, Vol.551, p.215972, Article 215972</ispartof><rights>2022 The Authors</rights><rights>Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.</rights><rights>2022. The Authors</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c390t-3f9335a6902ff98d1133da4d29fda2ebc347ea1c5621f13a4fa9c09cfc16a4b3</citedby><cites>FETCH-LOGICAL-c390t-3f9335a6902ff98d1133da4d29fda2ebc347ea1c5621f13a4fa9c09cfc16a4b3</cites><orcidid>0000-0001-9750-1810</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.canlet.2022.215972$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/36265653$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Du, Yuxin</creatorcontrib><creatorcontrib>Cai, Yun</creatorcontrib><creatorcontrib>Lv, Yan</creatorcontrib><creatorcontrib>Zhang, Lishen</creatorcontrib><creatorcontrib>Yang, Hao</creatorcontrib><creatorcontrib>Liu, Quanzhong</creatorcontrib><creatorcontrib>Hong, Ming</creatorcontrib><creatorcontrib>Teng, Yue</creatorcontrib><creatorcontrib>Tang, Weiyan</creatorcontrib><creatorcontrib>Ma, Rong</creatorcontrib><creatorcontrib>Wu, Jianqiu</creatorcontrib><creatorcontrib>Wu, Jianzhong</creatorcontrib><creatorcontrib>Wang, Qianghu</creatorcontrib><creatorcontrib>Chen, Hongshan</creatorcontrib><creatorcontrib>Li, Kening</creatorcontrib><creatorcontrib>Feng, Jifeng</creatorcontrib><title>Single-cell RNA sequencing unveils the communications between malignant T and myeloid cells contributing to tumor growth and immunosuppression in cutaneous T-cell lymphoma</title><title>Cancer letters</title><addtitle>Cancer Lett</addtitle><description>Cutaneous T cell lymphoma (CTCL) is characterized by the accumulation of malignant T cells in the skin. However, advanced CTCL pathophysiology remains elusive and therapeutic options are limited due to the high intratumoral heterogeneity and complicated tumor microenvironment (TME). By comparing the single-cell RNA-seq (scRNA-seq) data from advanced CTCL patients and healthy controls (HCs), we showed that CTCL had a higher enrichment of T/NK and myeloid cells. Subpopulations of T cells (CXCR3+, GNLY+, CREM+, and MKI67+ T cells), with high proliferation, stemness, and copy number variation (CNV) levels, contribute to the malignancy of CTCL. Besides, CCL13+ monocytes/macrophages and LAMP3+ cDC cells were enriched and mediated the immunosuppression via inhibitory interactions with malignant T cells, such as CD47-SIRPA, MIF-CD74, and CCR1-CCL18. Notably, elevated expressions of S100A9 and its receptor TLR4, as well as the activation of downstream toll-like receptor and NF-κB pathway were observed in both malignant cells and myeloid cells in CTCL. Cell co-culture experiments further confirmed that the interaction between malignant CTCL cells and macrophages contributed to tumor growth via S100A9 upregulation and NF-kb activation. Our results showed that blocking the S100A9-TLR4 interaction using tasquinimod could inactivate the NF-κB pathway and inhibit the growth of CTCL tumor cells, and trigger cell apoptosis. Collectively, our study revealed a landscape of immunosuppressive TME mediated by interactions between malignant T cells and myeloid cells, and provided novel targets and potential treatment strategies for advanced CTCL patients.
•CTCL has a higher enrichment of T and myeloid cells compared with healthy controls (HCs).•T cell subpopulations with high proliferation, stemness and CNV levels, contribute to the malignancy of CTCL.•CCL13+ mono/macrophages and LAMP3+ cDC cells interact with malignant T cells to shape the immunosuppression of CTCL.•NF-κB pathway induced by S100A9 and TLR4 interaction is activated in both malignant and myeloid cells in CTCL.•Blocking the S100A9-TLR4 interaction could inactivate the NF-κB pathway and inhibit the growth of CTCL tumor cells.</description><subject>Apoptosis</subject><subject>CC chemokine receptors</subject><subject>CCL18 protein</subject><subject>CCR1 protein</subject><subject>Cell culture</subject><subject>Cell proliferation</subject><subject>Copy number</subject><subject>Cutaneous T cell lymphoma</subject><subject>CXCR3 protein</subject><subject>Cytotoxicity</subject><subject>DNA Copy Number Variations</subject><subject>Ecosystems</subject><subject>Enzymes</subject><subject>Humans</subject><subject>Immunosuppression</subject><subject>Immunosuppression Therapy</subject><subject>Intratumoral heterogeneity</subject><subject>Lymphocytes</subject><subject>Lymphocytes T</subject><subject>Lymphoma</subject><subject>Lymphoma, T-Cell, Cutaneous - drug therapy</subject><subject>Lymphoma, T-Cell, Cutaneous - genetics</subject><subject>Lymphoma, T-Cell, Cutaneous - pathology</subject><subject>Macrophages</subject><subject>Malignancy</subject><subject>Medical prognosis</subject><subject>Monocytes</subject><subject>Myeloid cells</subject><subject>Myeloid Cells - metabolism</subject><subject>NF-kappa B - genetics</subject><subject>NF-κB protein</subject><subject>Patients</subject><subject>S100A9</subject><subject>Sequence Analysis, RNA</subject><subject>Skin Neoplasms - pathology</subject><subject>Statistical analysis</subject><subject>T-cell lymphoma</subject><subject>TLR4 protein</subject><subject>Toll-Like Receptor 4 - genetics</subject><subject>Toll-like receptors</subject><subject>Tumor cells</subject><subject>Tumor Microenvironment</subject><issn>0304-3835</issn><issn>1872-7980</issn><issn>1872-7980</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kcuKFDEUhoMoTjv6BiIBN26qza1uG2EYnFEYFLT3IZU61Z2mkrS5zNDP5EuaskYXLlwFDt_583M-hF5TsqWENu-PW63cDGnLCGNbRuu-ZU_QhnYtq9q-I0_RhnAiKt7x-gK9iPFICKlFWz9HF7xhTd3UfIN-fjduP0OlYZ7xty9XOMKPDE6XKc7uHswccToA1t7a7IxWyXgX8QDpAcBhq2azd8olvMPKjdieYfZmxEtcLEsuBTPktKQlj1O2PuB98A_p8Bs3S6iP-XQKEGNJxsZhnZNy4HPEu7XWfLang7fqJXo2qTnCq8f3Eu1uPu6uP1V3X28_X1_dVZr3JFV86jmvVdMTNk19N1LK-ajEyPppVAwGzUULiuq6YXSiXIlJ9Zr0etK0UWLgl-jdGnsKvtwiJmlNXIqsrSRrWdsI0YmmoG__QY8-B1fKLVRfk1awtlBipXTwMQaY5CkYq8JZUiIXl_IoV5dycSlXl2XtzWN4HiyMf5f-yCvAhxWAcox7A0FGbYo7GE0AneTozf9_-AUdK7Yy</recordid><startdate>20221228</startdate><enddate>20221228</enddate><creator>Du, Yuxin</creator><creator>Cai, Yun</creator><creator>Lv, Yan</creator><creator>Zhang, Lishen</creator><creator>Yang, Hao</creator><creator>Liu, Quanzhong</creator><creator>Hong, Ming</creator><creator>Teng, Yue</creator><creator>Tang, Weiyan</creator><creator>Ma, Rong</creator><creator>Wu, Jianqiu</creator><creator>Wu, Jianzhong</creator><creator>Wang, Qianghu</creator><creator>Chen, Hongshan</creator><creator>Li, Kening</creator><creator>Feng, Jifeng</creator><general>Elsevier B.V</general><general>Elsevier Limited</general><scope>6I.</scope><scope>AAFTH</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>7TO</scope><scope>7U9</scope><scope>H94</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0001-9750-1810</orcidid></search><sort><creationdate>20221228</creationdate><title>Single-cell RNA sequencing unveils the communications between malignant T and myeloid cells contributing to tumor growth and immunosuppression in cutaneous T-cell lymphoma</title><author>Du, Yuxin ; Cai, Yun ; Lv, Yan ; Zhang, Lishen ; Yang, Hao ; Liu, Quanzhong ; Hong, Ming ; Teng, Yue ; Tang, Weiyan ; Ma, Rong ; Wu, Jianqiu ; Wu, Jianzhong ; Wang, Qianghu ; Chen, Hongshan ; Li, Kening ; Feng, Jifeng</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c390t-3f9335a6902ff98d1133da4d29fda2ebc347ea1c5621f13a4fa9c09cfc16a4b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Apoptosis</topic><topic>CC chemokine receptors</topic><topic>CCL18 protein</topic><topic>CCR1 protein</topic><topic>Cell culture</topic><topic>Cell proliferation</topic><topic>Copy number</topic><topic>Cutaneous T cell lymphoma</topic><topic>CXCR3 protein</topic><topic>Cytotoxicity</topic><topic>DNA Copy Number Variations</topic><topic>Ecosystems</topic><topic>Enzymes</topic><topic>Humans</topic><topic>Immunosuppression</topic><topic>Immunosuppression Therapy</topic><topic>Intratumoral heterogeneity</topic><topic>Lymphocytes</topic><topic>Lymphocytes T</topic><topic>Lymphoma</topic><topic>Lymphoma, T-Cell, Cutaneous - drug therapy</topic><topic>Lymphoma, T-Cell, Cutaneous - genetics</topic><topic>Lymphoma, T-Cell, Cutaneous - pathology</topic><topic>Macrophages</topic><topic>Malignancy</topic><topic>Medical prognosis</topic><topic>Monocytes</topic><topic>Myeloid cells</topic><topic>Myeloid Cells - metabolism</topic><topic>NF-kappa B - genetics</topic><topic>NF-κB protein</topic><topic>Patients</topic><topic>S100A9</topic><topic>Sequence Analysis, RNA</topic><topic>Skin Neoplasms - pathology</topic><topic>Statistical analysis</topic><topic>T-cell lymphoma</topic><topic>TLR4 protein</topic><topic>Toll-Like Receptor 4 - genetics</topic><topic>Toll-like receptors</topic><topic>Tumor cells</topic><topic>Tumor Microenvironment</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Du, Yuxin</creatorcontrib><creatorcontrib>Cai, Yun</creatorcontrib><creatorcontrib>Lv, Yan</creatorcontrib><creatorcontrib>Zhang, Lishen</creatorcontrib><creatorcontrib>Yang, Hao</creatorcontrib><creatorcontrib>Liu, Quanzhong</creatorcontrib><creatorcontrib>Hong, Ming</creatorcontrib><creatorcontrib>Teng, Yue</creatorcontrib><creatorcontrib>Tang, Weiyan</creatorcontrib><creatorcontrib>Ma, Rong</creatorcontrib><creatorcontrib>Wu, Jianqiu</creatorcontrib><creatorcontrib>Wu, Jianzhong</creatorcontrib><creatorcontrib>Wang, Qianghu</creatorcontrib><creatorcontrib>Chen, Hongshan</creatorcontrib><creatorcontrib>Li, Kening</creatorcontrib><creatorcontrib>Feng, Jifeng</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>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>MEDLINE - Academic</collection><jtitle>Cancer letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Du, Yuxin</au><au>Cai, Yun</au><au>Lv, Yan</au><au>Zhang, Lishen</au><au>Yang, Hao</au><au>Liu, Quanzhong</au><au>Hong, Ming</au><au>Teng, Yue</au><au>Tang, Weiyan</au><au>Ma, Rong</au><au>Wu, Jianqiu</au><au>Wu, Jianzhong</au><au>Wang, Qianghu</au><au>Chen, Hongshan</au><au>Li, Kening</au><au>Feng, Jifeng</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Single-cell RNA sequencing unveils the communications between malignant T and myeloid cells contributing to tumor growth and immunosuppression in cutaneous T-cell lymphoma</atitle><jtitle>Cancer letters</jtitle><addtitle>Cancer Lett</addtitle><date>2022-12-28</date><risdate>2022</risdate><volume>551</volume><spage>215972</spage><pages>215972-</pages><artnum>215972</artnum><issn>0304-3835</issn><issn>1872-7980</issn><eissn>1872-7980</eissn><abstract>Cutaneous T cell lymphoma (CTCL) is characterized by the accumulation of malignant T cells in the skin. However, advanced CTCL pathophysiology remains elusive and therapeutic options are limited due to the high intratumoral heterogeneity and complicated tumor microenvironment (TME). By comparing the single-cell RNA-seq (scRNA-seq) data from advanced CTCL patients and healthy controls (HCs), we showed that CTCL had a higher enrichment of T/NK and myeloid cells. Subpopulations of T cells (CXCR3+, GNLY+, CREM+, and MKI67+ T cells), with high proliferation, stemness, and copy number variation (CNV) levels, contribute to the malignancy of CTCL. Besides, CCL13+ monocytes/macrophages and LAMP3+ cDC cells were enriched and mediated the immunosuppression via inhibitory interactions with malignant T cells, such as CD47-SIRPA, MIF-CD74, and CCR1-CCL18. Notably, elevated expressions of S100A9 and its receptor TLR4, as well as the activation of downstream toll-like receptor and NF-κB pathway were observed in both malignant cells and myeloid cells in CTCL. Cell co-culture experiments further confirmed that the interaction between malignant CTCL cells and macrophages contributed to tumor growth via S100A9 upregulation and NF-kb activation. Our results showed that blocking the S100A9-TLR4 interaction using tasquinimod could inactivate the NF-κB pathway and inhibit the growth of CTCL tumor cells, and trigger cell apoptosis. Collectively, our study revealed a landscape of immunosuppressive TME mediated by interactions between malignant T cells and myeloid cells, and provided novel targets and potential treatment strategies for advanced CTCL patients.
•CTCL has a higher enrichment of T and myeloid cells compared with healthy controls (HCs).•T cell subpopulations with high proliferation, stemness and CNV levels, contribute to the malignancy of CTCL.•CCL13+ mono/macrophages and LAMP3+ cDC cells interact with malignant T cells to shape the immunosuppression of CTCL.•NF-κB pathway induced by S100A9 and TLR4 interaction is activated in both malignant and myeloid cells in CTCL.•Blocking the S100A9-TLR4 interaction could inactivate the NF-κB pathway and inhibit the growth of CTCL tumor cells.</abstract><cop>Ireland</cop><pub>Elsevier B.V</pub><pmid>36265653</pmid><doi>10.1016/j.canlet.2022.215972</doi><orcidid>https://orcid.org/0000-0001-9750-1810</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Apoptosis CC chemokine receptors CCL18 protein CCR1 protein Cell culture Cell proliferation Copy number Cutaneous T cell lymphoma CXCR3 protein Cytotoxicity DNA Copy Number Variations Ecosystems Enzymes Humans Immunosuppression Immunosuppression Therapy Intratumoral heterogeneity Lymphocytes Lymphocytes T Lymphoma Lymphoma, T-Cell, Cutaneous - drug therapy Lymphoma, T-Cell, Cutaneous - genetics Lymphoma, T-Cell, Cutaneous - pathology Macrophages Malignancy Medical prognosis Monocytes Myeloid cells Myeloid Cells - metabolism NF-kappa B - genetics NF-κB protein Patients S100A9 Sequence Analysis, RNA Skin Neoplasms - pathology Statistical analysis T-cell lymphoma TLR4 protein Toll-Like Receptor 4 - genetics Toll-like receptors Tumor cells Tumor Microenvironment |
title | Single-cell RNA sequencing unveils the communications between malignant T and myeloid cells contributing to tumor growth and immunosuppression in cutaneous T-cell lymphoma |
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