title: CD4+ T cells elicit host immune responses to MHC class II-negative ovarian cancer through CCL5 secretion and CD40-mediated licensing of dendritic cells.
abstract: T cell adoptive transfer strategies that have produced clinical remissions against specific tumors have so far produced disappointing results against ovarian cancer. Recent evidence suggests that adoptively transferred CD4(+) T cells can trigger endogenous immune responses in particular patients with ovarian cancer through unknown mechanisms. However, conflicting reports suggest that ovarian cancer-infiltrating CD4(+) T cells are associated with negative outcomes. In this study, we elucidate the phenotypic attributes that enable polyclonal CD4(+) T cells briefly primed against tumor Ags to induce therapeutically relevant endogenous antitumor immune responses. Our results unveil a therapeutic mechanism whereby tumor-primed CD4(+) T cells transferred into ovarian cancer-bearing mice secrete high levels of CCL5, which recruits endogenous CCR5(+) dendritic cells to tumor locations and activate them through CD40-CD40L interactions. These newly matured dendritic cells are then able to prime tumor-specific endogenous CD8(+) T cells, which mediate long-term protection. Correspondingly, administration of tumor-primed CD4(+) T cells significantly delayed progression of MHC class II(-) ovarian cancers, similarly to CD8(+) T cells only, and directly activated wild-type but not CD40-deficient dendritic cells recruited to the tumor microenvironment. Our results unveil a CCL5- and CD40L-dependent mechanism of transferring immunity from exogenously activated CD4(+) T cells to tumor-exposed host cells, resulting in sustained antitumor effects. Our data provide a mechanistic rationale for incorporating tumor-reactive CD4(+) T cells in adoptive cell transfer immunotherapies against ovarian cancer and underscore the importance of optimizing immunotherapeutic strategies for the specific microenvironment of individual tumors.
authors.affiliation: Department of Microbiology and Immunology, Dartmouth Medical School, Lebanon, NH 03756, USA.
authors.forename: Yolanda C
authors.initials: YC
authors.lastname: Nesbeth
authors.forename: Diana G
authors.initials: DG
authors.lastname: Martinez
authors.forename: Seiko
authors.initials: S
authors.lastname: Toraya
authors.forename: Uciane K
authors.initials: UK
authors.lastname: Scarlett
authors.forename: Juan R
authors.initials: JR
authors.lastname: Cubillos-Ruiz
authors.forename: Melanie R
authors.initials: MR
authors.lastname: Rutkowski
authors.forename: Jose R
authors.initials: JR
authors.lastname: Conejo-Garcia
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D019013:CD40 Antigens / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D023201:CD40 Ligand / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000637:transplantation; D018827:Carcinoma, Lewis Lung; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000008:administration & dosage / Q000378:metabolism* / Q000502:physiology; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D016219:Immunotherapy, Adoptive / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010051:Ovarian Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D019713:Receptors, CCR5 / Q000096:biosynthesis / Q000502:physiology
chemical_list: D019013:CD40 Antigens; C503460:Ccl5 protein, mouse; D018946:Chemokine CCL5; D000949:Histocompatibility Antigens Class II; D019713:Receptors, CCR5; D023201:CD40 Ligand
references.citation: Nature. 1998 Jun 4;393(6684):478-80
references.pmid: 9624004
references.citation: Nat Rev Cancer. 2003 Sep;3(9):666-75
references.pmid: 12951585
references.citation: J Exp Med. 2008 Oct 27;205(11):2561-74
references.pmid: 18838544
references.citation: Nat Rev Cancer. 2008 Apr;8(4):299-308
references.pmid: 18354418
references.citation: Nat Rev Immunol. 2006 May;6(5):383-93
references.pmid: 16622476
references.citation: J Exp Med. 1996 Aug 1;184(2):747-52
references.pmid: 8760829
references.citation: Blood. 2005 Jan 15;105(2):679-81
references.pmid: 15358628
references.citation: Curr Opin Immunol. 2009 Apr;21(2):233-40
references.pmid: 19304471
references.citation: J Exp Med. 2010 Mar 15;207(3):637-50
references.pmid: 20156971
references.citation: Immunol Rev. 2009 May;229(1):152-72
references.pmid: 19426221
references.citation: J Immunol. 2006 Nov 1;177(9):6548-59
references.pmid: 17056587
references.citation: Science. 2003 Apr 11;300(5617):337-9
references.pmid: 12690201
references.citation: Cancer Res. 2008 Sep 15;68(18):7684-91
references.pmid: 18768667
references.citation: Cancer Cell. 2002 Feb;1(1):53-62
references.pmid: 12086888
references.citation: N Engl J Med. 2008 Jun 19;358(25):2698-703
references.pmid: 18565862
references.citation: Science. 2002 Oct 25;298(5594):850-4
references.pmid: 12242449
references.citation: Clin Immunol. 2009 Dec;133(3):333-52
references.pmid: 19762283
references.citation: Cancer Res. 2009 Sep 15;69(18):7329-37
references.pmid: 19738057
references.citation: N Engl J Med. 2003 Jan 16;348(3):203-13
references.pmid: 12529460
references.citation: Carcinogenesis. 2000 Apr;21(4):585-91
references.pmid: 10753190
references.citation: Cancer Res. 2009 Aug 1;69(15):6256-64
references.pmid: 19622771
references.citation: Nat Med. 2004 Sep;10(9):950-8
references.pmid: 15334073
references.citation: J Exp Med. 1985 May 1;161(5):1122-34
references.pmid: 3921652
references.citation: J Immunol. 2000 Jan 15;164(2):562-5
references.pmid: 10623795
references.citation: Cancer Res. 2009 Aug 1;69(15):6331-8
references.pmid: 19602595
references.citation: Nature. 2004 Jul 8;430(6996):150-1
references.pmid: 15241396
references.citation: Semin Oncol. 2007 Dec;34(6):524-31
references.pmid: 18083376
references.citation: Nat Rev Immunol. 2009 Oct;9(10):704-16
references.pmid: 19859065
references.citation: J Clin Invest. 2009 Aug;119(8):2231-44
references.pmid: 19620771
references.citation: Proc Natl Acad Sci U S A. 2005 Dec 20;102(51):18538-43
references.pmid: 16344461
references.citation: J Exp Med. 2010 Mar 15;207(3):651-67
references.pmid: 20156973
references.citation: J Immunol. 1984 Sep;133(3):1671-6
references.pmid: 6205091
references.citation: J Clin Oncol. 2008 Nov 10;26(32):5233-9
references.pmid: 18809613
references.citation: Curr Opin Immunol. 2009 Apr;21(2):200-8
references.pmid: 19285848
references.citation: Cell Cycle. 2005 Aug;4(8):1004-6
references.pmid: 15970711