title: IL-15 in tumor microenvironment causes rejection of large established tumors by T cells in a noncognate T cell receptor-dependent manner.
abstract: A major challenge of cancer immunotherapy is the persistence and outgrowth of subpopulations that lose expression of the target antigen. IL-15 is a potent cytokine that can promote organ-specific autoimmunity when up-regulated on tissue cells. Here we report that T cells eradicated 2-wk-old solid tumors that expressed IL-15, eliminating antigen-negative cells. In contrast, control tumors that lacked IL-15 expression consistently relapsed. Interestingly, even tumors lacking expression of cognate antigen were rejected when expressing IL-15, indicating that rejection after adoptive T-cell transfer was independent of cognate antigen expression. Nevertheless, the T-cell receptor of the transferred T cells influenced the outcome, consistent with the notion that T-cell receptor activation and effector status determine whether IL-15 can confer lymphokine killer activity-like properties to T cells. The effect was limited to the microenvironment of tumors expressing IL-15; there were no noticeable effects on contralateral tumors lacking IL-15. Taken together, these results indicate that expression of IL-15 in the tumor microenvironment may prevent the escape of antigen loss variants and subsequent tumor recurrence by enabling T cells to eliminate cancer cells lacking cognate antigen expression in a locally restricted manner.
authors: Committee on Immunology, University of Chicago, Chicago, IL 60637, USA.
authors: Rebecca Berlant
authors: RB
authors: Liu
authors: Boris
authors: B
authors: Engels
authors: Karin
authors: K
authors: Schreiber
authors: Cezary
authors: C
authors: Ciszewski
authors: Andrea
authors: A
authors: Schietinger
authors: Hans
authors: H
authors: Schreiber
authors: Bana
authors: B
authors: Jabri
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism; D015551:Autoimmunity; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D019409:Interleukin-15 / Q000235:genetics / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009369:Neoplasms / Q000378:metabolism*; D054353:Perforin / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D013154:Spleen / Q000166:cytology; D017154:Stromal Cells / Q000166:cytology; D059016:Tumor Microenvironment
chemical_list: D000951:Antigens, Neoplasm; D019409:Interleukin-15; D011948:Receptors, Antigen, T-Cell; D054353:Perforin; D049452:Green Fluorescent Proteins
keywords: NK receptors; NKG2D
references: J Immunol. 2010 Apr 15;184(8):4215-27
references: 20237297
references: Proc Natl Acad Sci U S A. 1998 Oct 13;95(21):12492-7
references: 9770513
references: J Exp Med. 1994 Oct 1;180(4):1395-403
references: 7523571
references: Immunity. 2002 Dec;17(6):737-47
references: 12479820
references: Nat Rev Immunol. 2009 Dec;9(12):858-70
references: 19935805
references: J Immunol. 2008 Feb 15;180(4):2099-106
references: 18250415
references: J Leukoc Biol. 1995 May;57(5):763-6
references: 7759955
references: Cancer Res. 1998 Aug 15;58(16):3491-4
references: 9721846
references: Arthritis Res Ther. 2004;6(4):174-7
references: 15225362
references: J Immunol. 2001 Nov 15;167(10):5527-30
references: 11698420
references: Blood. 2005 Jan 15;105(2):721-7
references: 15367431
references: Cancer Res. 2008 Apr 15;68(8):2972-83
references: 18413767
references: Cancer Res. 2004 Nov 1;64(21):8062-7
references: 15520217
references: J Immunol. 2008 Jun 15;180(12):7818-26
references: 18523245
references: Nat Med. 2004 Mar;10(3):294-8
references: 14981514
references: Cancer Res. 2012 Apr 15;72(8):1964-74
references: 22374983
references: Cytokine Growth Factor Rev. 2006 Aug;17(4):259-80
references: 16815076
references: N Engl J Med. 2003 Jan 16;348(3):203-13
references: 12529460
references: J Exp Med. 2008 May 12;205(5):1213-25
references: 18458113
references: Cancer Res. 1995 Nov 1;55(21):4988-94
references: 7585540
references: Eur J Immunol. 2008 Oct;38(10):2874-85
references: 18825743
references: Proc Natl Acad Sci U S A. 2005 Dec 20;102(51):18538-43
references: 16344461
references: Proc Natl Acad Sci U S A. 2002 Dec 10;99(25):16168-73
references: 12427970
references: Nat Med. 2006 Mar;12(3):335-41
references: 16474399
references: Cancer Immunol Immunother. 2012 Aug;61(8):1269-77
references: 22274776
references: N Engl J Med. 2005 Dec 22;353(25):2654-66
references: 16371631
references: Lancet. 2003 Aug 2;362(9381):383-91
references: 12907013
references: J Exp Med. 1983 Mar 1;157(3):1040-52
references: 6187879
references: Proc Natl Acad Sci U S A. 2004 Feb 17;101(7):1969-74
references: 14762166
references: J Exp Med. 2001 Jan 15;193(2):219-31
references: 11208862
references: Immunity. 2000 Jun;12(6):721-7
references: 10894171
references: Eur J Immunol. 2006 Nov;36(11):3052-9
references: 17051621
references: Proc Natl Acad Sci U S A. 2003 Aug 5;100(16):9452-7
references: 12878725
references: J Exp Med. 2009 Mar 16;206(3):707-19
references: 19237603
references: J Clin Invest. 2008 Apr;118(4):1398-404
references: 18317595
references: Immunity. 2004 Sep;21(3):367-77
references: 15357948
references: J Exp Med. 1982 Feb 1;155(2):557-73
references: 6977009
references: Immunity. 2004 Sep;21(3):357-66
references: 15357947
references: Proc Natl Acad Sci U S A. 2007 Jan 9;104(2):588-93
references: 17202253