title: Murine CD27(-) Vγ6(+) γδ T cells producing IL-17A promote ovarian cancer growth via mobilization of protumor small peritoneal macrophages.
abstract: Cancer-associated inflammation mobilizes a variety of leukocyte populations that can inhibit or enhance tumor cell growth in situ. These subsets include γδ T cells, which can infiltrate tumors and typically provide large amounts of antitumor cytokines, such as IFN-γ. By contrast, we report here that in a well-established transplantable (ID8 cell line) model of peritoneal/ovarian cancer, γδ T cells promote tumor cell growth. γδ T cells accumulated in the peritoneal cavity in response to tumor challenge and could be visualized within solid tumor foci. Functional characterization of tumor-associated γδ T cells revealed preferential production of interleukin-17A (IL-17), rather than IFN-γ. Consistent with this finding, both T cell receptor (TCR)δ-deficient and IL-17-deficient mice displayed reduced ID8 tumor growth compared with wild-type animals. IL-17 production by γδ T cells in the tumor environment was essentially restricted to a highly proliferative CD27((-)) subset that expressed Vγ6 instead of the more common Vγ1 and Vγ4 TCR chains. The preferential expansion of IL-17-secreting CD27((-)) Vγ6((+)) γδ T cells associated with the selective mobilization of unconventional small peritoneal macrophages (SPMs) that, in comparison with large peritoneal macrophages, were enriched for IL-17 receptor A, and for protumor and proangiogenic molecular mediators, which were up-regulated by IL-17. Importantly, SPMs were uniquely and directly capable of promoting ovarian cancer cell proliferation. Collectively, this work identifies an IL-17-dependent lymphoid/myeloid cross-talk involving γδ T cells and SPMs that promotes tumor cell growth and thus counteracts cancer immunosurveillance.
authors.affiliation: Blizard Institute, Barts and The London School of Medicine, Queen Mary University of London, London E1 2AT, United Kingdom; Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal; Graduate Program in Areas of Basic and Applied Biology, Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, 4050-313 Porto, Portugal; and.
authors.forename: Margarida
authors.initials: M
authors.lastname: Rei
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal;
authors.forename: Natacha
authors.initials: N
authors.lastname: Gonçalves-Sousa
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal;
authors.forename: Telma
authors.initials: T
authors.lastname: Lança
authors.affiliation: Centre for Cancer and Inflammation, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, United Kingdom.
authors.forename: Richard G
authors.initials: RG
authors.lastname: Thompson
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal;
authors.forename: Sofia
authors.initials: S
authors.lastname: Mensurado
authors.affiliation: Centre for Cancer and Inflammation, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, United Kingdom.
authors.forename: Frances R
authors.initials: FR
authors.lastname: Balkwill
authors.affiliation: Centre for Cancer and Inflammation, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, United Kingdom.
authors.forename: Hagen
authors.initials: H
authors.lastname: Kulbe
authors.affiliation: Blizard Institute, Barts and The London School of Medicine, Queen Mary University of London, London E1 2AT, United Kingdom; bssantos@fm.ul.pt d.pennington@qmul.ac.uk.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Pennington
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal; bssantos@fm.ul.pt d.pennington@qmul.ac.uk.
authors.forename: Bruno
authors.initials: B
authors.lastname: Silva-Santos
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D005260:Female; D018836:Inflammation Mediators / Q000378:metabolism; D020381:Interleukin-17 / Q000096:biosynthesis*; D016246:Lymphocytes, Tumor-Infiltrating / Q000145:classification / Q000276:immunology / Q000473:pathology; D017737:Macrophages, Peritoneal / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic; D010051:Ovarian Neoplasms / Q000276:immunology* / Q000473:pathology; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D053722:Receptors, Interleukin-17 / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000473:pathology; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: C491673:Il17ra protein, mouse; D018836:Inflammation Mediators; D020381:Interleukin-17; D016692:Receptors, Antigen, T-Cell, gamma-delta; D053722:Receptors, Interleukin-17; C000589613:T-cell receptor Vgamma6, mouse; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7
keywords: gamma-delta T cells; tumor immunology
references.citation: Scand J Immunol. 2007 Aug-Sep;66(2-3):320-8
references.pmid: 17635809
references.citation: Cancer Cell. 2005 Sep;8(3):211-26
references.pmid: 16169466
references.citation: J Exp Med. 2003 Aug 4;198(3):433-42
references.pmid: 12900519
references.citation: J Immunol. 2011 Sep 1;187(5):2783-93
references.pmid: 21813772
references.citation: Proc Natl Acad Sci U S A. 2010 Feb 9;107(6):2568-73
references.pmid: 20133793
references.citation: Cancer Res. 2014 Apr 1;74(7):1969-82
references.pmid: 24525743
references.citation: Blood. 2007 Jun 15;109(12):5276-85
references.pmid: 17327411
references.citation: Eur J Immunol. 2011 Jan;41(1):195-201
references.pmid: 21182090
references.citation: Eur J Immunol. 2012 Mar;42(3):726-36
references.pmid: 22161142
references.citation: Nat Rev Immunol. 2003 Oct;3(10):791-800
references.pmid: 14502271
references.citation: J Exp Med. 1999 Nov 15;190(10):1375-82
references.pmid: 10562313
references.citation: J Immunol. 2012 Nov 15;189(10):5029-36
references.pmid: 23034170
references.citation: Cell. 2014 May 8;157(4):832-44
references.pmid: 24792964
references.citation: Trends Immunol. 2011 Dec;32(12):567-73
references.pmid: 22056207
references.citation: Cancer Res. 2012 Jan 1;72(1):66-75
references.pmid: 22065722
references.citation: Immunity. 2013 Jul 25;39(1):184-95
references.pmid: 23890071
references.citation: Eur J Immunol. 2010 Jul;40(7):1927-37
references.pmid: 20397212
references.citation: J Immunol. 2005 Oct 15;175(8):5481-8
references.pmid: 16210656
references.citation: J Exp Med. 2009 Jul 6;206(7):1457-64
references.pmid: 19564351
references.citation: Nat Immunol. 2013 Oct;14(10):1093-1100
references.pmid: 23995235
references.citation: J Immunol. 2010 Apr 15;184(8):4479-87
references.pmid: 20228199
references.citation: J Exp Med. 2011 Mar 14;208(3):491-503
references.pmid: 21383056
references.citation: Eur J Immunol. 2009 Jul;39(7):1794-806
references.pmid: 19544311
references.citation: Cell Mol Immunol. 2013 Jan;10(1):35-41
references.pmid: 23241899
references.citation: Cancer Res. 2013 Dec 1;73(23):6900-12
references.pmid: 23975756
references.citation: Front Immunol. 2013 Dec 05;4:431
references.pmid: 24367369
references.citation: Mol Cancer Ther. 2007 Jul;6(7):1993-2002
references.pmid: 17620429
references.citation: Oncoimmunology. 2012 Aug 1;1(5):717-725
references.pmid: 22934263
references.citation: Proc Natl Acad Sci U S A. 2010 Mar 23;107(12):5540-4
references.pmid: 20212110
references.citation: Blood. 2003 Apr 1;101(7):2620-7
references.pmid: 12411307
references.citation: J Thorac Oncol. 2012 Jul;7(7):1091-100
references.pmid: 22534817
references.citation: J Immunol. 2013 Jun 15;190(12):6673-80
references.pmid: 23686489
references.citation: Blood. 2009 Jul 9;114(2):357-9
references.pmid: 19289853
references.citation: J Immunol. 2010 Dec 1;185(11):6421-6425
references.pmid: 21037088
references.citation: J Immunol. 2008 Sep 1;181(5):3456-63
references.pmid: 18714018
references.citation: Immunity. 2009 Aug 21;31(2):331-41
references.pmid: 19682929
references.citation: Proc Natl Acad Sci U S A. 2012 Oct 23;109(43):17549-54
references.pmid: 23047700
references.citation: Immunity. 2012 Mar 23;36(3):362-73
references.pmid: 22406269
references.citation: Blood. 2011 Jul 7;118(1):129-38
references.pmid: 21505189
references.citation: Cancer Res. 2010 Jul 1;70(13):5270-80
references.pmid: 20530679
references.citation: Biochim Biophys Acta. 2014 Apr;1845(2):117-25
references.pmid: 24388871
references.citation: Nat Rev Immunol. 2011 Sep 23;11(10):702-11
references.pmid: 21941296
references.citation: Immunity. 2009 Aug 21;31(2):184-96
references.pmid: 19699170
references.citation: Eur J Immunol. 2010 Jul;40(7):1873-6
references.pmid: 20549671
references.citation: Immunity. 2014 May 15;40(5):785-800
references.pmid: 24816404
references.citation: Cancer Res. 2007 Jan 15;67(2):585-92
references.pmid: 17234767
references.citation: Trends Immunol. 2012 May;33(5):199-206
references.pmid: 22364810
references.citation: J Immunol. 2005 Nov 1;175(9):6177-89
references.pmid: 16237115
references.citation: J Leukoc Biol. 2004 Jan;75(1):68-75
references.pmid: 14525969
references.citation: J Immunol. 2010 Mar 1;184(5):2281-8
references.pmid: 20118280
references.citation: Blood. 2008 Jul 15;112(2):362-73
references.pmid: 18354038
references.citation: J Clin Invest. 2009 Oct;119(10):3011-23
references.pmid: 19741298
references.citation: J Immunol. 2009 Mar 15;182(6):3884-91
references.pmid: 19265168
references.citation: Eur J Immunol. 2013 Aug;43(8):1988-94
references.pmid: 23928962
references.citation: Science. 2001 Oct 19;294(5542):605-9
references.pmid: 11567106
references.citation: J Immunol. 2008 May 1;180(9):6044-53
references.pmid: 18424725
references.citation: Immunity. 2009 Nov 20;31(5):787-98
references.pmid: 19879162
references.citation: Eur J Immunol. 2011 Jan;41(1):246-51
references.pmid: 21182095
references.citation: J Exp Med. 2004 Mar 15;199(6):879-84
references.pmid: 15007091
references.citation: Blood. 2010 Mar 25;115(12):2407-11
references.pmid: 20101024
references.citation: Cancer Res. 2010 Dec 15;70(24):10024-7
references.pmid: 21159627
references.citation: Eur J Immunol. 2013 Oct;43(10):2696-706
references.pmid: 23843079
references.citation: Haematologica. 2010 Aug;95(8):1397-404
references.pmid: 20220060
references.citation: Nat Immunol. 2009 Apr;10(4):427-36
references.pmid: 19270712
references.citation: Blood. 2009 Jul 23;114(4):901-14
references.pmid: 19383967
references.citation: J Immunol. 2010 Jun 15;184(12):7268-80
references.pmid: 20483730
references.citation: J Pathol. 2012 Jun;227(2):136-45
references.pmid: 22322968
references.citation: J Immunol. 2013 Nov 1;191(9):4665-75
references.pmid: 24078688