Dysfunctional Vγ9Vδ2 T cells are negative prognosticators and markers of dysregulated mevalonate pathway activity in chronic lymphocytic leukemia cells
The role of Vγ9Vδ2 T cells in chronic lymphocytic leukemia (CLL) is unexplored, although these cells have a natural inclination to react against B-cell malignancies. Proliferation induced by zoledronic acid was used as a surrogate of γδ TCR-dependent stimulation to functionally interrogate Vγ9Vδ2 T...
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| Veröffentlicht in: | Blood 2012-10, Vol.120 (16), p.3271-3279 |
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| creator | Coscia, Marta Vitale, Candida Peola, Silvia Foglietta, Myriam Rigoni, Micol Griggio, Valentina Castella, Barbara Angelini, Daniela Chiaretti, Sabina Riganti, Chiara Guarini, Anna Drandi, Daniela Ladetto, Marco Bosia, Amalia Foà, Robin Battistini, Luca Boccadoro, Mario Fournié, Jean-Jacques Massaia, Massimo |
| description | The role of Vγ9Vδ2 T cells in chronic lymphocytic leukemia (CLL) is unexplored, although these cells have a natural inclination to react against B-cell malignancies. Proliferation induced by zoledronic acid was used as a surrogate of γδ TCR-dependent stimulation to functionally interrogate Vγ9Vδ2 T cells in 106 untreated CLL patients. This assay permitted the identification of responder and low-responder (LR) patients. The LR status was associated with greater baseline counts of Vγ9Vδ2 T cells and to the expansion of the effector memory and terminally differentiated effector memory subsets. The tumor immunoglobulin heavy chain variable region was more frequently unmutated in CLL cells of LR patients, and the mevalonate pathway, which generates Vγ9Vδ2 TCR ligands, was more active in unmutated CLL cells. In addition, greater numbers of circulating regulatory T cells were detected in LR patients. In multivariate analysis, the LR condition was an independent predictor of shorter time-to-first treatment. Accordingly, the time-to-first treatment was significantly shorter in patients with greater baseline numbers of total Vγ9Vδ2 T cells and effector memory and terminally differentiated effector memory subpopulations. These results unveil a clinically relevant in vivo relationship between the mevalonate pathway activity of CLL cells and dys-functional Vγ9Vδ2 T cells. |
| doi_str_mv | 10.1182/blood-2012-03-417519 |
| format | Article |
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Proliferation induced by zoledronic acid was used as a surrogate of γδ TCR-dependent stimulation to functionally interrogate Vγ9Vδ2 T cells in 106 untreated CLL patients. This assay permitted the identification of responder and low-responder (LR) patients. The LR status was associated with greater baseline counts of Vγ9Vδ2 T cells and to the expansion of the effector memory and terminally differentiated effector memory subsets. The tumor immunoglobulin heavy chain variable region was more frequently unmutated in CLL cells of LR patients, and the mevalonate pathway, which generates Vγ9Vδ2 TCR ligands, was more active in unmutated CLL cells. In addition, greater numbers of circulating regulatory T cells were detected in LR patients. In multivariate analysis, the LR condition was an independent predictor of shorter time-to-first treatment. Accordingly, the time-to-first treatment was significantly shorter in patients with greater baseline numbers of total Vγ9Vδ2 T cells and effector memory and terminally differentiated effector memory subpopulations. These results unveil a clinically relevant in vivo relationship between the mevalonate pathway activity of CLL cells and dys-functional Vγ9Vδ2 T cells.</description><identifier>ISSN: 0006-4971</identifier><identifier>EISSN: 1528-0020</identifier><identifier>DOI: 10.1182/blood-2012-03-417519</identifier><identifier>PMID: 22932792</identifier><language>eng</language><publisher>Washington, DC: Elsevier Inc</publisher><subject>Adult ; Aged ; Aged, 80 and over ; Biological and medical sciences ; Biomarkers, Tumor - genetics ; Biomarkers, Tumor - metabolism ; Blotting, Western ; Bone Density Conservation Agents - pharmacology ; Case-Control Studies ; Cell Differentiation - drug effects ; Cell Differentiation - immunology ; Cells, Cultured ; Diphosphonates - pharmacology ; Female ; Follow-Up Studies ; Gene Expression Profiling ; Geranyltranstransferase - antagonists & inhibitors ; Hematologic and hematopoietic diseases ; Humans ; Imidazoles - pharmacology ; Immunologic Memory - immunology ; Leukemia, Lymphocytic, Chronic, B-Cell - immunology ; Leukemia, Lymphocytic, Chronic, B-Cell - metabolism ; Leukemia, Lymphocytic, Chronic, B-Cell - mortality ; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis ; Lymphocyte Activation - immunology ; Male ; Medical sciences ; Mevalonic Acid - metabolism ; Middle Aged ; Oligonucleotide Array Sequence Analysis ; Real-Time Polymerase Chain Reaction ; Receptors, Antigen, T-Cell, gamma-delta - immunology ; Reverse Transcriptase Polymerase Chain Reaction ; RNA, Messenger - genetics ; Signal Transduction ; Survival Rate ; T-Lymphocyte Subsets - immunology ; T-Lymphocyte Subsets - metabolism ; T-Lymphocyte Subsets - pathology ; T-Lymphocytes, Regulatory - immunology ; Zoledronic Acid</subject><ispartof>Blood, 2012-10, Vol.120 (16), p.3271-3279</ispartof><rights>2012 American Society of Hematology</rights><rights>2015 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3539-2200cdaf90fbf6e524039b286cb2bf676dd3c9b3e3be8ec28f315481adae11a33</citedby><cites>FETCH-LOGICAL-c3539-2200cdaf90fbf6e524039b286cb2bf676dd3c9b3e3be8ec28f315481adae11a33</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,781,785,27929,27930</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=26507511$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22932792$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Coscia, Marta</creatorcontrib><creatorcontrib>Vitale, Candida</creatorcontrib><creatorcontrib>Peola, Silvia</creatorcontrib><creatorcontrib>Foglietta, Myriam</creatorcontrib><creatorcontrib>Rigoni, Micol</creatorcontrib><creatorcontrib>Griggio, Valentina</creatorcontrib><creatorcontrib>Castella, Barbara</creatorcontrib><creatorcontrib>Angelini, Daniela</creatorcontrib><creatorcontrib>Chiaretti, Sabina</creatorcontrib><creatorcontrib>Riganti, Chiara</creatorcontrib><creatorcontrib>Guarini, Anna</creatorcontrib><creatorcontrib>Drandi, Daniela</creatorcontrib><creatorcontrib>Ladetto, Marco</creatorcontrib><creatorcontrib>Bosia, Amalia</creatorcontrib><creatorcontrib>Foà, Robin</creatorcontrib><creatorcontrib>Battistini, Luca</creatorcontrib><creatorcontrib>Boccadoro, Mario</creatorcontrib><creatorcontrib>Fournié, Jean-Jacques</creatorcontrib><creatorcontrib>Massaia, Massimo</creatorcontrib><title>Dysfunctional Vγ9Vδ2 T cells are negative prognosticators and markers of dysregulated mevalonate pathway activity in chronic lymphocytic leukemia cells</title><title>Blood</title><addtitle>Blood</addtitle><description>The role of Vγ9Vδ2 T cells in chronic lymphocytic leukemia (CLL) is unexplored, although these cells have a natural inclination to react against B-cell malignancies. Proliferation induced by zoledronic acid was used as a surrogate of γδ TCR-dependent stimulation to functionally interrogate Vγ9Vδ2 T cells in 106 untreated CLL patients. This assay permitted the identification of responder and low-responder (LR) patients. The LR status was associated with greater baseline counts of Vγ9Vδ2 T cells and to the expansion of the effector memory and terminally differentiated effector memory subsets. The tumor immunoglobulin heavy chain variable region was more frequently unmutated in CLL cells of LR patients, and the mevalonate pathway, which generates Vγ9Vδ2 TCR ligands, was more active in unmutated CLL cells. In addition, greater numbers of circulating regulatory T cells were detected in LR patients. In multivariate analysis, the LR condition was an independent predictor of shorter time-to-first treatment. Accordingly, the time-to-first treatment was significantly shorter in patients with greater baseline numbers of total Vγ9Vδ2 T cells and effector memory and terminally differentiated effector memory subpopulations. These results unveil a clinically relevant in vivo relationship between the mevalonate pathway activity of CLL cells and dys-functional Vγ9Vδ2 T cells.</description><subject>Adult</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Biological and medical sciences</subject><subject>Biomarkers, Tumor - genetics</subject><subject>Biomarkers, Tumor - metabolism</subject><subject>Blotting, Western</subject><subject>Bone Density Conservation Agents - pharmacology</subject><subject>Case-Control Studies</subject><subject>Cell Differentiation - drug effects</subject><subject>Cell Differentiation - immunology</subject><subject>Cells, Cultured</subject><subject>Diphosphonates - pharmacology</subject><subject>Female</subject><subject>Follow-Up Studies</subject><subject>Gene Expression Profiling</subject><subject>Geranyltranstransferase - antagonists & inhibitors</subject><subject>Hematologic and hematopoietic diseases</subject><subject>Humans</subject><subject>Imidazoles - pharmacology</subject><subject>Immunologic Memory - immunology</subject><subject>Leukemia, Lymphocytic, Chronic, B-Cell - immunology</subject><subject>Leukemia, Lymphocytic, Chronic, B-Cell - metabolism</subject><subject>Leukemia, Lymphocytic, Chronic, B-Cell - mortality</subject><subject>Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis</subject><subject>Lymphocyte Activation - immunology</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Mevalonic Acid - metabolism</subject><subject>Middle Aged</subject><subject>Oligonucleotide Array Sequence Analysis</subject><subject>Real-Time Polymerase Chain Reaction</subject><subject>Receptors, Antigen, T-Cell, gamma-delta - immunology</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>RNA, Messenger - genetics</subject><subject>Signal Transduction</subject><subject>Survival Rate</subject><subject>T-Lymphocyte Subsets - immunology</subject><subject>T-Lymphocyte Subsets - metabolism</subject><subject>T-Lymphocyte Subsets - pathology</subject><subject>T-Lymphocytes, Regulatory - immunology</subject><subject>Zoledronic Acid</subject><issn>0006-4971</issn><issn>1528-0020</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kUtuFDEQhi0EIkPgBgh5g8SmwY9-bpBQeEqR2IRsrWq7esak2x5s90R9FM4B58iZ8NAD7Fi5VP6q_qr6CXnK2UvOW_GqH703hWBcFEwWJW8q3t0jG16JtmBMsPtkwxiri7Jr-Bl5FONXxngpRfWQnAnRSdF0YkO-v13iMDudrHcw0uu7H9313U9Br6jGcYwUAlKHW0j2gHQf_Nb5mKyG5EP-dIZOEG4wx36gZokBt_MICXMeDzDmnimXQdrdwkIhqxxsWqh1VO-Cd1bTcZn2O6-XdIxxvsHJwir9mDwYYIz45PSeky_v311dfCwuP3_4dPHmstCykl0hBGPawNCxoR9qrETJZNeLtta9yImmNkbqrpcoe2xRi3aQvCpbDgaQc5DynLxY--btvs0Yk5psPE4ADv0cFee8bFglZZ3RckV18DHvOqh9sPkAi-JMHU1Rv01RR1MUk2o1JZc9OynM_YTmb9EfFzLw_ARA1DAOAZy28R9XVyw34pl7vXKY73GwGFTUFp1GYwPqpIy3_5_kF912sIk</recordid><startdate>20121018</startdate><enddate>20121018</enddate><creator>Coscia, Marta</creator><creator>Vitale, Candida</creator><creator>Peola, Silvia</creator><creator>Foglietta, Myriam</creator><creator>Rigoni, Micol</creator><creator>Griggio, Valentina</creator><creator>Castella, Barbara</creator><creator>Angelini, Daniela</creator><creator>Chiaretti, Sabina</creator><creator>Riganti, Chiara</creator><creator>Guarini, Anna</creator><creator>Drandi, Daniela</creator><creator>Ladetto, Marco</creator><creator>Bosia, Amalia</creator><creator>Foà, Robin</creator><creator>Battistini, Luca</creator><creator>Boccadoro, Mario</creator><creator>Fournié, Jean-Jacques</creator><creator>Massaia, Massimo</creator><general>Elsevier Inc</general><general>Americain Society of Hematology</general><scope>6I.</scope><scope>AAFTH</scope><scope>IQODW</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>7X8</scope></search><sort><creationdate>20121018</creationdate><title>Dysfunctional Vγ9Vδ2 T cells are negative prognosticators and markers of dysregulated mevalonate pathway activity in chronic lymphocytic leukemia cells</title><author>Coscia, Marta ; Vitale, Candida ; Peola, Silvia ; Foglietta, Myriam ; Rigoni, Micol ; Griggio, Valentina ; Castella, Barbara ; Angelini, Daniela ; Chiaretti, Sabina ; Riganti, Chiara ; Guarini, Anna ; Drandi, Daniela ; Ladetto, Marco ; Bosia, Amalia ; Foà, Robin ; Battistini, Luca ; Boccadoro, Mario ; Fournié, Jean-Jacques ; Massaia, Massimo</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3539-2200cdaf90fbf6e524039b286cb2bf676dd3c9b3e3be8ec28f315481adae11a33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Adult</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Biological and medical sciences</topic><topic>Biomarkers, Tumor - genetics</topic><topic>Biomarkers, Tumor - metabolism</topic><topic>Blotting, Western</topic><topic>Bone Density Conservation Agents - pharmacology</topic><topic>Case-Control Studies</topic><topic>Cell Differentiation - drug effects</topic><topic>Cell Differentiation - immunology</topic><topic>Cells, Cultured</topic><topic>Diphosphonates - pharmacology</topic><topic>Female</topic><topic>Follow-Up Studies</topic><topic>Gene Expression Profiling</topic><topic>Geranyltranstransferase - antagonists & inhibitors</topic><topic>Hematologic and hematopoietic diseases</topic><topic>Humans</topic><topic>Imidazoles - pharmacology</topic><topic>Immunologic Memory - immunology</topic><topic>Leukemia, Lymphocytic, Chronic, B-Cell - immunology</topic><topic>Leukemia, Lymphocytic, Chronic, B-Cell - metabolism</topic><topic>Leukemia, Lymphocytic, Chronic, B-Cell - mortality</topic><topic>Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis</topic><topic>Lymphocyte Activation - immunology</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Mevalonic Acid - metabolism</topic><topic>Middle Aged</topic><topic>Oligonucleotide Array Sequence Analysis</topic><topic>Real-Time Polymerase Chain Reaction</topic><topic>Receptors, Antigen, T-Cell, gamma-delta - immunology</topic><topic>Reverse Transcriptase Polymerase Chain Reaction</topic><topic>RNA, Messenger - genetics</topic><topic>Signal Transduction</topic><topic>Survival Rate</topic><topic>T-Lymphocyte Subsets - immunology</topic><topic>T-Lymphocyte Subsets - metabolism</topic><topic>T-Lymphocyte Subsets - pathology</topic><topic>T-Lymphocytes, Regulatory - immunology</topic><topic>Zoledronic Acid</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Coscia, Marta</creatorcontrib><creatorcontrib>Vitale, Candida</creatorcontrib><creatorcontrib>Peola, Silvia</creatorcontrib><creatorcontrib>Foglietta, Myriam</creatorcontrib><creatorcontrib>Rigoni, Micol</creatorcontrib><creatorcontrib>Griggio, Valentina</creatorcontrib><creatorcontrib>Castella, Barbara</creatorcontrib><creatorcontrib>Angelini, Daniela</creatorcontrib><creatorcontrib>Chiaretti, Sabina</creatorcontrib><creatorcontrib>Riganti, Chiara</creatorcontrib><creatorcontrib>Guarini, Anna</creatorcontrib><creatorcontrib>Drandi, Daniela</creatorcontrib><creatorcontrib>Ladetto, Marco</creatorcontrib><creatorcontrib>Bosia, Amalia</creatorcontrib><creatorcontrib>Foà, Robin</creatorcontrib><creatorcontrib>Battistini, Luca</creatorcontrib><creatorcontrib>Boccadoro, Mario</creatorcontrib><creatorcontrib>Fournié, Jean-Jacques</creatorcontrib><creatorcontrib>Massaia, Massimo</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Pascal-Francis</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><jtitle>Blood</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Coscia, Marta</au><au>Vitale, Candida</au><au>Peola, Silvia</au><au>Foglietta, Myriam</au><au>Rigoni, Micol</au><au>Griggio, Valentina</au><au>Castella, Barbara</au><au>Angelini, Daniela</au><au>Chiaretti, Sabina</au><au>Riganti, Chiara</au><au>Guarini, Anna</au><au>Drandi, Daniela</au><au>Ladetto, Marco</au><au>Bosia, Amalia</au><au>Foà, Robin</au><au>Battistini, Luca</au><au>Boccadoro, Mario</au><au>Fournié, Jean-Jacques</au><au>Massaia, Massimo</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Dysfunctional Vγ9Vδ2 T cells are negative prognosticators and markers of dysregulated mevalonate pathway activity in chronic lymphocytic leukemia cells</atitle><jtitle>Blood</jtitle><addtitle>Blood</addtitle><date>2012-10-18</date><risdate>2012</risdate><volume>120</volume><issue>16</issue><spage>3271</spage><epage>3279</epage><pages>3271-3279</pages><issn>0006-4971</issn><eissn>1528-0020</eissn><abstract>The role of Vγ9Vδ2 T cells in chronic lymphocytic leukemia (CLL) is unexplored, although these cells have a natural inclination to react against B-cell malignancies. Proliferation induced by zoledronic acid was used as a surrogate of γδ TCR-dependent stimulation to functionally interrogate Vγ9Vδ2 T cells in 106 untreated CLL patients. This assay permitted the identification of responder and low-responder (LR) patients. The LR status was associated with greater baseline counts of Vγ9Vδ2 T cells and to the expansion of the effector memory and terminally differentiated effector memory subsets. The tumor immunoglobulin heavy chain variable region was more frequently unmutated in CLL cells of LR patients, and the mevalonate pathway, which generates Vγ9Vδ2 TCR ligands, was more active in unmutated CLL cells. In addition, greater numbers of circulating regulatory T cells were detected in LR patients. In multivariate analysis, the LR condition was an independent predictor of shorter time-to-first treatment. Accordingly, the time-to-first treatment was significantly shorter in patients with greater baseline numbers of total Vγ9Vδ2 T cells and effector memory and terminally differentiated effector memory subpopulations. These results unveil a clinically relevant in vivo relationship between the mevalonate pathway activity of CLL cells and dys-functional Vγ9Vδ2 T cells.</abstract><cop>Washington, DC</cop><pub>Elsevier Inc</pub><pmid>22932792</pmid><doi>10.1182/blood-2012-03-417519</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Blood, 2012-10, Vol.120 (16), p.3271-3279 |
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| source | MEDLINE; EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
| subjects | Adult Aged Aged, 80 and over Biological and medical sciences Biomarkers, Tumor - genetics Biomarkers, Tumor - metabolism Blotting, Western Bone Density Conservation Agents - pharmacology Case-Control Studies Cell Differentiation - drug effects Cell Differentiation - immunology Cells, Cultured Diphosphonates - pharmacology Female Follow-Up Studies Gene Expression Profiling Geranyltranstransferase - antagonists & inhibitors Hematologic and hematopoietic diseases Humans Imidazoles - pharmacology Immunologic Memory - immunology Leukemia, Lymphocytic, Chronic, B-Cell - immunology Leukemia, Lymphocytic, Chronic, B-Cell - metabolism Leukemia, Lymphocytic, Chronic, B-Cell - mortality Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis Lymphocyte Activation - immunology Male Medical sciences Mevalonic Acid - metabolism Middle Aged Oligonucleotide Array Sequence Analysis Real-Time Polymerase Chain Reaction Receptors, Antigen, T-Cell, gamma-delta - immunology Reverse Transcriptase Polymerase Chain Reaction RNA, Messenger - genetics Signal Transduction Survival Rate T-Lymphocyte Subsets - immunology T-Lymphocyte Subsets - metabolism T-Lymphocyte Subsets - pathology T-Lymphocytes, Regulatory - immunology Zoledronic Acid |
| title | Dysfunctional Vγ9Vδ2 T cells are negative prognosticators and markers of dysregulated mevalonate pathway activity in chronic lymphocytic leukemia cells |
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