title: Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma.
abstract: Treatment with monoclonal antibody specific for cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), an inhibitory receptor expressed by T lymphocytes, has emerged as an effective therapy for the treatment of metastatic melanoma. Although subject to debate, current models favor a mechanism of activity involving blockade of the inhibitory activity of CTLA-4 on both effector (T eff) and regulatory (T reg) T cells, resulting in enhanced antitumor effector T cell activity capable of inducing tumor regression. We demonstrate, however, that the activity of anti-CTLA-4 antibody on the T reg cell compartment is mediated via selective depletion of T reg cells within tumor lesions. Importantly, T reg cell depletion is dependent on the presence of Fcγ receptor-expressing macrophages within the tumor microenvironment, indicating that T reg cells are depleted in trans in a context-dependent manner. Our results reveal further mechanistic insight into the activity of anti-CTLA-4-based cancer immunotherapy, and illustrate the importance of specific features of the local tumor environment on the final outcome of antibody-based immunomodulatory therapies.
authors.affiliation: Department of Immunology, M D Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Tyler R
authors.initials: TR
authors.lastname: Simpson
authors.forename: Fubin
authors.initials: F
authors.lastname: Li
authors.forename: Welby
authors.initials: W
authors.lastname: Montalvo-Ortiz
authors.forename: Manuel A
authors.initials: MA
authors.lastname: Sepulveda
authors.forename: Katharina
authors.initials: K
authors.lastname: Bergerhoff
authors.forename: Frederick
authors.initials: F
authors.lastname: Arce
authors.forename: Claire
authors.initials: C
authors.lastname: Roddie
authors.forename: Jake Y
authors.initials: JY
authors.lastname: Henry
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Jedd D
authors.initials: JD
authors.lastname: Wolchok
authors.forename: Karl S
authors.initials: KS
authors.lastname: Peggs
authors.forename: Jeffrey V
authors.initials: JV
authors.lastname: Ravetch
authors.forename: James P
authors.initials: JP
authors.lastname: Allison
authors.forename: Sergio A
authors.initials: SA
authors.lastname: Quezada
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology / Q000627:therapeutic use; D039481:CD11b Antigen / Q000378:metabolism; D015704:CD4 Antigens / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002999:Clone Cells; D053222:Fas Ligand Protein / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000627:therapeutic use; D008198:Lymph Nodes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D018655:Lymphocyte Count; D008212:Lymphocyte Depletion; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D008545:Melanoma / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D010586:Phagocytes / Q000187:drug effects / Q000276:immunology; D017452:Receptors, IgG / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D016896:Treatment Outcome; D059016:Tumor Microenvironment / Q000187:drug effects / Q000276:immunology
chemical_list: D019138:Antibodies, Blocking; D039481:CD11b Antigen; D015704:CD4 Antigens; D060908:CTLA-4 Antigen; D053222:Fas Ligand Protein; C522404:Fcgr4 protein, mouse; D017452:Receptors, IgG; D053221:TNF-Related Apoptosis-Inducing Ligand; D016178:Granulocyte-Macrophage Colony-Stimulating Factor
references.citation: J Exp Med. 2006 Mar 20;203(3):743-53
references.pmid: 16520392
references.citation: J Immunol. 2008 Nov 15;181(10):6829-36
references.pmid: 18981101
references.citation: J Exp Med. 2000 Apr 17;191(8):1293-302
references.pmid: 10770797
references.citation: Science. 2008 Oct 10;322(5899):271-5
references.pmid: 18845758
references.citation: J Exp Med. 2008 Sep 1;205(9):2125-38
references.pmid: 18725522
references.citation: J Exp Med. 2010 Mar 15;207(3):651-67
references.pmid: 20156973
references.citation: Cancer Res. 2009 Oct 1;69(19):7747-55
references.pmid: 19738077
references.citation: Proc Natl Acad Sci U S A. 2008 Feb 26;105(8):3005-10
references.pmid: 18287062
references.citation: J Leukoc Biol. 2004 Dec;76(6):1093-103
references.pmid: 15466916
references.citation: Springer Semin Immunopathol. 2006 Dec;28(4):351-64
references.pmid: 17091246
references.citation: Nat Immunol. 2009 Sep;10(9):1000-7
references.pmid: 19633673
references.citation: N Engl J Med. 2010 Aug 19;363(8):711-23
references.pmid: 20525992
references.citation: Cancer Immunol Res. 2013 Jul;1(1):32-42
references.pmid: 24777248
references.citation: J Exp Med. 1999 Aug 2;190(3):355-66
references.pmid: 10430624
references.citation: Cancer Res. 2010 Oct 15;70(20):7788-99
references.pmid: 20924102
references.citation: Nat Rev Immunol. 2008 Jan;8(1):34-47
references.pmid: 18064051
references.citation: Immunol Rev. 2011 May;241(1):104-18
references.pmid: 21488893
references.citation: Glycobiology. 2007 Jan;17(1):104-18
references.pmid: 17012310
references.citation: J Am Soc Nephrol. 2006 Jun;17(6):1665-72
references.pmid: 16641148
references.citation: J Exp Med. 2001 Sep 17;194(6):823-32
references.pmid: 11560997
references.citation: Blood. 2008 Jan 1;111(1):229-35
references.pmid: 17921346
references.citation: Nat Immunol. 2003 Apr;4(4):330-6
references.pmid: 12612578
references.citation: Blood. 2007 Dec 15;110(13):4370-2
references.pmid: 17909075
references.citation: Blood. 2008 Aug 15;112(4):1175-83
references.pmid: 18523152
references.citation: Blood. 1994 Jan 15;83(2):435-45
references.pmid: 7506951
references.citation: J Immunol Methods. 2001 Feb 1;248(1-2):103-11
references.pmid: 11223072
references.citation: Proc Natl Acad Sci U S A. 2010 Nov 9;107(45):19396-401
references.pmid: 20974962
references.citation: J Exp Med. 2000 Jul 17;192(2):295-302
references.pmid: 10899916
references.citation: Cancer Immunol Immunother. 2007 Nov;56(11):1743-53
references.pmid: 17487490
references.citation: Cell. 1994 Feb 11;76(3):519-29
references.pmid: 8313472
references.citation: Immunity. 2005 May;22(5):539-50
references.pmid: 15894272
references.citation: Nat Immunol. 2007 Feb;8(2):191-7
references.pmid: 17136045
references.citation: Cancer Immunol Immunother. 2010 Sep;59(9):1367-77
references.pmid: 20480365
references.citation: Brain Res. 1998 Dec 7;813(2):241-53
references.pmid: 9838143
references.citation: Blood. 2008 Jul 15;112(2):362-73
references.pmid: 18354038
references.citation: J Exp Med. 2004 Jun 21;199(12):1659-69
references.pmid: 15210744
references.citation: Immunity. 2005 Jul;23(1):41-51
references.pmid: 16039578
references.citation: Proc Natl Acad Sci U S A. 1998 Jan 20;95(2):652-6
references.pmid: 9435247
references.citation: Cancer Res. 2012 Jan 15;72(2):430-9
references.pmid: 22108823
references.citation: J Exp Med. 1996 Jun 1;183(6):2533-40
references.pmid: 8676074
references.citation: J Clin Invest. 2006 Jul;116(7):1935-45
references.pmid: 16778987
references.citation: J Exp Med. 2010 Mar 15;207(3):637-50
references.pmid: 20156971
references.citation: J Immunol. 2009 Jan 1;182(1):274-82
references.pmid: 19109158
references.citation: N Engl J Med. 2011 Jun 30;364(26):2517-26
references.pmid: 21639810
references.citation: Expert Opin Biol Ther. 2008 Jun;8(6):759-68
references.pmid: 18476787
references.citation: J Immunol. 2008 Dec 15;181(12):8745-52
references.pmid: 19050295
references.citation: Proc Natl Acad Sci U S A. 2009 Feb 24;106(8):2729-34
references.pmid: 19202079
references.citation: J Exp Med. 2009 Aug 3;206(8):1717-25
references.pmid: 19581407
references.citation: Cancer Res. 2007 Feb 1;67(3):1291-8
references.pmid: 17283166
references.citation: J Immunother. 2009 Jan;32(1):12-21
references.pmid: 19307989
references.citation: J Immunol. 2011 Nov 15;187(10):5293-8
references.pmid: 21976773
references.citation: J Immunol. 2006 Oct 1;177(7):4376-83
references.pmid: 16982872
references.citation: J Exp Med. 2008 Apr 14;205(4):825-39
references.pmid: 18362171
references.citation: J Exp Med. 2012 Oct 22;209(11):2113-26
references.pmid: 23008334
references.citation: Proc Natl Acad Sci U S A. 2008 Sep 30;105(39):14987-92
references.pmid: 18818309
references.citation: Immunity. 1999 Oct;11(4):483-93
references.pmid: 10549630
references.citation: J Exp Med. 2000 Jul 17;192(2):303-10
references.pmid: 10899917
references.citation: Eur J Immunol. 2010 Mar;40(3):780-6
references.pmid: 20039297
references.citation: J Immunol. 2005 Mar 1;174(5):2591-601
references.pmid: 15728465
references.citation: Science. 1996 Mar 22;271(5256):1734-6
references.pmid: 8596936