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Soluble IL6R Expressed by Myeloid Cells Reduces Tumor-Specific Th1 Differentiation and Drives Tumor Progression
IL6 produced by tumor cells promotes their survival, conferring a poor prognosis in patients with cancer. IL6 also contributes to immunosuppression of CD4 T cell-mediated antitumor effects. In this study, we focused on the impact of IL6 trans-signaling mediated by soluble IL6 receptors (sIL6R) expre...
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Published in: | Cancer research (Chicago, Ill.) Ill.), 2017-05, Vol.77 (9), p.2279-2291 |
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container_title | Cancer research (Chicago, Ill.) |
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creator | Tsukamoto, Hirotake Fujieda, Koji Hirayama, Masatoshi Ikeda, Tokunori Yuno, Akira Matsumura, Keiko Fukuma, Daiki Araki, Kimi Mizuta, Hiroshi Nakayama, Hideki Senju, Satoru Nishimura, Yasuharu |
description | IL6 produced by tumor cells promotes their survival, conferring a poor prognosis in patients with cancer. IL6 also contributes to immunosuppression of CD4
T cell-mediated antitumor effects. In this study, we focused on the impact of IL6 trans-signaling mediated by soluble IL6 receptors (sIL6R) expressed in tumor-bearing hosts. Higher levels of sIL6R circulating in blood were observed in tumor-bearing mice, whereas the systemic increase of sIL6R was not prominent in tumor-bearing mice with myeloid cell-specific conditional deletion of IL6R even when tumor cells produced sIL6R. Abundant sIL6R was released by CD11b
cells from tumor-bearing mice but not tumor-free mice. Notably, IL6-mediated defects in Th1 differentiation, T-cell helper activity for tumor-specific CD8
T cells, and downstream antitumor effects were rescued by myeloid-specific deletion of sIL6R. Expression of the T-cell transcription factor c-Maf was upregulated in CD4
T cells primed in tumor-bearing mice in an IL6-dependent manner. Investigations with c-Maf loss-of-function T cells revealed that c-Maf activity was responsible for IL6/sIL6R-induced Th1 suppression and defective T-cell-mediated antitumor responses. In patients with cancer, myeloid cell-derived sIL6R was also possibly associated with Th1 suppression and c-Maf expression. Our results argued that increased expression of sIL6R from myeloid cells and subsequent c-Maf induction were adverse events for counteracting tumor-specific Th1 generation. Overall, this work provides a mechanistic rationale for sIL6R targeting to improve the efficacy of T-cell-mediated cancer immunotherapy.
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doi_str_mv | 10.1158/0008-5472.can-16-2446 |
format | article |
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T cell-mediated antitumor effects. In this study, we focused on the impact of IL6 trans-signaling mediated by soluble IL6 receptors (sIL6R) expressed in tumor-bearing hosts. Higher levels of sIL6R circulating in blood were observed in tumor-bearing mice, whereas the systemic increase of sIL6R was not prominent in tumor-bearing mice with myeloid cell-specific conditional deletion of IL6R even when tumor cells produced sIL6R. Abundant sIL6R was released by CD11b
cells from tumor-bearing mice but not tumor-free mice. Notably, IL6-mediated defects in Th1 differentiation, T-cell helper activity for tumor-specific CD8
T cells, and downstream antitumor effects were rescued by myeloid-specific deletion of sIL6R. Expression of the T-cell transcription factor c-Maf was upregulated in CD4
T cells primed in tumor-bearing mice in an IL6-dependent manner. Investigations with c-Maf loss-of-function T cells revealed that c-Maf activity was responsible for IL6/sIL6R-induced Th1 suppression and defective T-cell-mediated antitumor responses. In patients with cancer, myeloid cell-derived sIL6R was also possibly associated with Th1 suppression and c-Maf expression. Our results argued that increased expression of sIL6R from myeloid cells and subsequent c-Maf induction were adverse events for counteracting tumor-specific Th1 generation. Overall, this work provides a mechanistic rationale for sIL6R targeting to improve the efficacy of T-cell-mediated cancer immunotherapy.
.</description><identifier>ISSN: 0008-5472</identifier><identifier>EISSN: 1538-7445</identifier><identifier>DOI: 10.1158/0008-5472.can-16-2446</identifier><identifier>PMID: 28235765</identifier><language>eng</language><publisher>United States: American Association for Cancer Research, Inc</publisher><subject>Animals ; Antitumor activity ; Auditory defects ; Blood circulation ; c-Maf protein ; Cancer ; Cancer immunotherapy ; Carcinogenesis - genetics ; CD11b antigen ; CD4 antigen ; CD4-Positive T-Lymphocytes - pathology ; CD8 antigen ; Clonal deletion ; Gene Expression Regulation, Neoplastic ; Humans ; Immunosuppression ; Immunotherapy ; Interleukin 6 ; Interleukin 6 receptors ; Interleukin-6 - genetics ; Lymphocytes ; Lymphocytes T ; Medical prognosis ; Mice ; Molecular Targeted Therapy ; Myeloid cells ; Myeloid Cells - metabolism ; Myeloid Cells - pathology ; Neoplasms - genetics ; Neoplasms - pathology ; Proto-Oncogene Proteins c-maf - genetics ; Receptors, Interleukin-6 - genetics ; Th1 Cells ; Tumor cells</subject><ispartof>Cancer research (Chicago, Ill.), 2017-05, Vol.77 (9), p.2279-2291</ispartof><rights>2017 American Association for Cancer Research.</rights><rights>Copyright American Association for Cancer Research, Inc. May 1, 2017</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c535t-c78be918895220fe75fb8b04507477f481385bfc9f7f79e33802efdbbe9a79df3</citedby><cites>FETCH-LOGICAL-c535t-c78be918895220fe75fb8b04507477f481385bfc9f7f79e33802efdbbe9a79df3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28235765$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Tsukamoto, Hirotake</creatorcontrib><creatorcontrib>Fujieda, Koji</creatorcontrib><creatorcontrib>Hirayama, Masatoshi</creatorcontrib><creatorcontrib>Ikeda, Tokunori</creatorcontrib><creatorcontrib>Yuno, Akira</creatorcontrib><creatorcontrib>Matsumura, Keiko</creatorcontrib><creatorcontrib>Fukuma, Daiki</creatorcontrib><creatorcontrib>Araki, Kimi</creatorcontrib><creatorcontrib>Mizuta, Hiroshi</creatorcontrib><creatorcontrib>Nakayama, Hideki</creatorcontrib><creatorcontrib>Senju, Satoru</creatorcontrib><creatorcontrib>Nishimura, Yasuharu</creatorcontrib><title>Soluble IL6R Expressed by Myeloid Cells Reduces Tumor-Specific Th1 Differentiation and Drives Tumor Progression</title><title>Cancer research (Chicago, Ill.)</title><addtitle>Cancer Res</addtitle><description>IL6 produced by tumor cells promotes their survival, conferring a poor prognosis in patients with cancer. IL6 also contributes to immunosuppression of CD4
T cell-mediated antitumor effects. In this study, we focused on the impact of IL6 trans-signaling mediated by soluble IL6 receptors (sIL6R) expressed in tumor-bearing hosts. Higher levels of sIL6R circulating in blood were observed in tumor-bearing mice, whereas the systemic increase of sIL6R was not prominent in tumor-bearing mice with myeloid cell-specific conditional deletion of IL6R even when tumor cells produced sIL6R. Abundant sIL6R was released by CD11b
cells from tumor-bearing mice but not tumor-free mice. Notably, IL6-mediated defects in Th1 differentiation, T-cell helper activity for tumor-specific CD8
T cells, and downstream antitumor effects were rescued by myeloid-specific deletion of sIL6R. Expression of the T-cell transcription factor c-Maf was upregulated in CD4
T cells primed in tumor-bearing mice in an IL6-dependent manner. Investigations with c-Maf loss-of-function T cells revealed that c-Maf activity was responsible for IL6/sIL6R-induced Th1 suppression and defective T-cell-mediated antitumor responses. In patients with cancer, myeloid cell-derived sIL6R was also possibly associated with Th1 suppression and c-Maf expression. Our results argued that increased expression of sIL6R from myeloid cells and subsequent c-Maf induction were adverse events for counteracting tumor-specific Th1 generation. Overall, this work provides a mechanistic rationale for sIL6R targeting to improve the efficacy of T-cell-mediated cancer immunotherapy.
.</description><subject>Animals</subject><subject>Antitumor activity</subject><subject>Auditory defects</subject><subject>Blood circulation</subject><subject>c-Maf protein</subject><subject>Cancer</subject><subject>Cancer immunotherapy</subject><subject>Carcinogenesis - genetics</subject><subject>CD11b antigen</subject><subject>CD4 antigen</subject><subject>CD4-Positive T-Lymphocytes - pathology</subject><subject>CD8 antigen</subject><subject>Clonal deletion</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Humans</subject><subject>Immunosuppression</subject><subject>Immunotherapy</subject><subject>Interleukin 6</subject><subject>Interleukin 6 receptors</subject><subject>Interleukin-6 - genetics</subject><subject>Lymphocytes</subject><subject>Lymphocytes T</subject><subject>Medical prognosis</subject><subject>Mice</subject><subject>Molecular Targeted Therapy</subject><subject>Myeloid cells</subject><subject>Myeloid Cells - metabolism</subject><subject>Myeloid Cells - pathology</subject><subject>Neoplasms - genetics</subject><subject>Neoplasms - pathology</subject><subject>Proto-Oncogene Proteins c-maf - genetics</subject><subject>Receptors, Interleukin-6 - genetics</subject><subject>Th1 Cells</subject><subject>Tumor cells</subject><issn>0008-5472</issn><issn>1538-7445</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><recordid>eNqFkU1P3DAQhi1EBVvgJ4AsceES6o9M7BzRQlukbYtgOVuJMwajbLzYG9T993XEx4FLTyNrnveVxg8hx5ydcw76G2NMF1AqcW6boeBVIcqy2iEzDlIXqixhl8w-mH3yNaWn_ATOYI_sCy0kqApmJNyFfmx7pNeL6pZe_V1HTAk72m7pry32wXd0jn2f6C12o8VEl-MqxOJujdY7b-nykdNL7xxGHDa-2fgw0Gbo6GX0L-80vYnhYerNy0PyxTV9wqO3eUDuv18t5z-LxZ8f1_OLRWFBwqawSrdYc61rEII5VOBa3bISmCqVcqXmUkPrbO2UUzVKqZlA17U51Ki6c_KAnL32rmN4HjFtzMonmy9pBgxjMrxmXAGrK_Z_VCsxfZZWGT39hD6FMQ75kFyopYCsRmYKXikbQ0oRnVlHv2ri1nBmJnlmEmMmMWZ-8dvwykzycu7krX1sV9h9pN5tyX__n5Si</recordid><startdate>20170501</startdate><enddate>20170501</enddate><creator>Tsukamoto, Hirotake</creator><creator>Fujieda, Koji</creator><creator>Hirayama, Masatoshi</creator><creator>Ikeda, Tokunori</creator><creator>Yuno, Akira</creator><creator>Matsumura, Keiko</creator><creator>Fukuma, Daiki</creator><creator>Araki, Kimi</creator><creator>Mizuta, Hiroshi</creator><creator>Nakayama, Hideki</creator><creator>Senju, Satoru</creator><creator>Nishimura, Yasuharu</creator><general>American Association for Cancer Research, Inc</general><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>7T5</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>20170501</creationdate><title>Soluble IL6R Expressed by Myeloid Cells Reduces Tumor-Specific Th1 Differentiation and Drives Tumor Progression</title><author>Tsukamoto, Hirotake ; Fujieda, Koji ; Hirayama, Masatoshi ; Ikeda, Tokunori ; Yuno, Akira ; Matsumura, Keiko ; Fukuma, Daiki ; Araki, Kimi ; Mizuta, Hiroshi ; Nakayama, Hideki ; Senju, Satoru ; Nishimura, Yasuharu</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c535t-c78be918895220fe75fb8b04507477f481385bfc9f7f79e33802efdbbe9a79df3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Animals</topic><topic>Antitumor activity</topic><topic>Auditory defects</topic><topic>Blood circulation</topic><topic>c-Maf protein</topic><topic>Cancer</topic><topic>Cancer immunotherapy</topic><topic>Carcinogenesis - genetics</topic><topic>CD11b antigen</topic><topic>CD4 antigen</topic><topic>CD4-Positive T-Lymphocytes - pathology</topic><topic>CD8 antigen</topic><topic>Clonal deletion</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Humans</topic><topic>Immunosuppression</topic><topic>Immunotherapy</topic><topic>Interleukin 6</topic><topic>Interleukin 6 receptors</topic><topic>Interleukin-6 - genetics</topic><topic>Lymphocytes</topic><topic>Lymphocytes T</topic><topic>Medical prognosis</topic><topic>Mice</topic><topic>Molecular Targeted Therapy</topic><topic>Myeloid cells</topic><topic>Myeloid Cells - metabolism</topic><topic>Myeloid Cells - pathology</topic><topic>Neoplasms - genetics</topic><topic>Neoplasms - pathology</topic><topic>Proto-Oncogene Proteins c-maf - genetics</topic><topic>Receptors, Interleukin-6 - genetics</topic><topic>Th1 Cells</topic><topic>Tumor cells</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Tsukamoto, Hirotake</creatorcontrib><creatorcontrib>Fujieda, Koji</creatorcontrib><creatorcontrib>Hirayama, Masatoshi</creatorcontrib><creatorcontrib>Ikeda, Tokunori</creatorcontrib><creatorcontrib>Yuno, Akira</creatorcontrib><creatorcontrib>Matsumura, Keiko</creatorcontrib><creatorcontrib>Fukuma, Daiki</creatorcontrib><creatorcontrib>Araki, Kimi</creatorcontrib><creatorcontrib>Mizuta, Hiroshi</creatorcontrib><creatorcontrib>Nakayama, Hideki</creatorcontrib><creatorcontrib>Senju, Satoru</creatorcontrib><creatorcontrib>Nishimura, Yasuharu</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Immunology Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Cancer research (Chicago, Ill.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Tsukamoto, Hirotake</au><au>Fujieda, Koji</au><au>Hirayama, Masatoshi</au><au>Ikeda, Tokunori</au><au>Yuno, Akira</au><au>Matsumura, Keiko</au><au>Fukuma, Daiki</au><au>Araki, Kimi</au><au>Mizuta, Hiroshi</au><au>Nakayama, Hideki</au><au>Senju, Satoru</au><au>Nishimura, Yasuharu</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Soluble IL6R Expressed by Myeloid Cells Reduces Tumor-Specific Th1 Differentiation and Drives Tumor Progression</atitle><jtitle>Cancer research (Chicago, Ill.)</jtitle><addtitle>Cancer Res</addtitle><date>2017-05-01</date><risdate>2017</risdate><volume>77</volume><issue>9</issue><spage>2279</spage><epage>2291</epage><pages>2279-2291</pages><issn>0008-5472</issn><eissn>1538-7445</eissn><abstract>IL6 produced by tumor cells promotes their survival, conferring a poor prognosis in patients with cancer. IL6 also contributes to immunosuppression of CD4
T cell-mediated antitumor effects. In this study, we focused on the impact of IL6 trans-signaling mediated by soluble IL6 receptors (sIL6R) expressed in tumor-bearing hosts. Higher levels of sIL6R circulating in blood were observed in tumor-bearing mice, whereas the systemic increase of sIL6R was not prominent in tumor-bearing mice with myeloid cell-specific conditional deletion of IL6R even when tumor cells produced sIL6R. Abundant sIL6R was released by CD11b
cells from tumor-bearing mice but not tumor-free mice. Notably, IL6-mediated defects in Th1 differentiation, T-cell helper activity for tumor-specific CD8
T cells, and downstream antitumor effects were rescued by myeloid-specific deletion of sIL6R. Expression of the T-cell transcription factor c-Maf was upregulated in CD4
T cells primed in tumor-bearing mice in an IL6-dependent manner. Investigations with c-Maf loss-of-function T cells revealed that c-Maf activity was responsible for IL6/sIL6R-induced Th1 suppression and defective T-cell-mediated antitumor responses. In patients with cancer, myeloid cell-derived sIL6R was also possibly associated with Th1 suppression and c-Maf expression. Our results argued that increased expression of sIL6R from myeloid cells and subsequent c-Maf induction were adverse events for counteracting tumor-specific Th1 generation. Overall, this work provides a mechanistic rationale for sIL6R targeting to improve the efficacy of T-cell-mediated cancer immunotherapy.
.</abstract><cop>United States</cop><pub>American Association for Cancer Research, Inc</pub><pmid>28235765</pmid><doi>10.1158/0008-5472.can-16-2446</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Animals Antitumor activity Auditory defects Blood circulation c-Maf protein Cancer Cancer immunotherapy Carcinogenesis - genetics CD11b antigen CD4 antigen CD4-Positive T-Lymphocytes - pathology CD8 antigen Clonal deletion Gene Expression Regulation, Neoplastic Humans Immunosuppression Immunotherapy Interleukin 6 Interleukin 6 receptors Interleukin-6 - genetics Lymphocytes Lymphocytes T Medical prognosis Mice Molecular Targeted Therapy Myeloid cells Myeloid Cells - metabolism Myeloid Cells - pathology Neoplasms - genetics Neoplasms - pathology Proto-Oncogene Proteins c-maf - genetics Receptors, Interleukin-6 - genetics Th1 Cells Tumor cells |
title | Soluble IL6R Expressed by Myeloid Cells Reduces Tumor-Specific Th1 Differentiation and Drives Tumor Progression |
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