NFAT1 supports tumor-induced anergy of CD4(+) T cells.

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  • Author(s): Abe BT;Abe BT; Shin DS; Mocholi E; Macian F
  • Source:
    Cancer research [Cancer Res] 2012 Sep 15; Vol. 72 (18), pp. 4642-51. Date of Electronic Publication: 2012 Aug 03.
  • Publication Type:
    Journal Article; Research Support, N.I.H., Extramural
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: American Association for Cancer Research Country of Publication: United States NLM ID: 2984705R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1538-7445 (Electronic) Linking ISSN: 00085472 NLM ISO Abbreviation: Cancer Res Subsets: MEDLINE
    • Publication Information:
      Publication: Baltimore, Md. : American Association for Cancer Research
      Original Publication: Chicago [etc.]
    • Subject Terms:
      CD4-Positive T-Lymphocytes/*immunology ; Clonal Anergy/*immunology ; Melanoma/*immunology ; Melanoma/*metabolism ; NFATC Transcription Factors/*immunology ; Tumor Escape/*immunology; Adoptive Transfer ; Animals ; Disease Models, Animal ; Enzyme-Linked Immunosorbent Assay ; Mice ; Mice, Transgenic ; NFATC Transcription Factors/metabolism ; Real-Time Polymerase Chain Reaction ; Tumor Microenvironment/physiology
    • Abstract:
      Cancer cells express antigens that elicit T cell-mediated responses, but these responses are limited during malignant progression by the development of immunosuppressive mechanisms in the tumor microenvironment that drive immune escape. T-cell hyporesponsiveness can be caused by clonal anergy or adaptive tolerance, but the pathophysiological roles of these processes in specific tumor contexts has yet to be understood. In CD4+ T cells, clonal anergy occurs when the T-cell receptor is activated in the absence of a costimulatory signal. Here we report that the key T-cell transcription factor NFAT mediates expression of anergy-associated genes in the context of cancer. Specifically, in a murine model of melanoma, we found that cancer cells induced anergy in antigen-specific CD4+ T-cell populations, resulting in defective production of several key effector cytokines. NFAT1 deficiency blunted the induction of anergy in tumor antigen-specific CD4+ T cells, enhancing antitumor responses. These investigations identified tumor-induced T-cell hyporesponsiveness as a form of clonal anergy, and they supported an important role for CD4+ T-cell anergy in driving immune escape. By illustrating the dependence of tumor-induced CD4+ T-cell anergy on NFAT1, our findings open the possibility of targeting this transcription factor to improve the efficacy of cancer immunotherapy or immunochemotherapy.
    • References:
      Cancer Res. 1999 Aug 1;59(15):3698-704. (PMID: 10446984)
      Proc Natl Acad Sci U S A. 1998 Feb 3;95(3):1178-83. (PMID: 9448305)
      J Immunol. 2000 Jan 15;164(2):562-5. (PMID: 10623795)
      Immunol Rev. 2009 Sep;231(1):225-40. (PMID: 19754900)
      Immunity. 2004 Aug;21(2):167-77. (PMID: 15308098)
      Nat Med. 1999 Jun;5(6):677-85. (PMID: 10371507)
      Blood. 2008 Jul 15;112(2):362-73. (PMID: 18354038)
      Immunity. 2009 Nov 20;31(5):787-98. (PMID: 19879162)
      Cancer Res. 2003 Dec 15;63(24):9007-15. (PMID: 14695219)
      Immunity. 1999 Oct;11(4):483-93. (PMID: 10549630)
      Am J Pathol. 1997 Feb;150(2):641-51. (PMID: 9033277)
      Blood. 2008 Jun 15;111(12):5457-66. (PMID: 18375791)
      Cell. 2006 Jul 28;126(2):375-87. (PMID: 16873067)
      Immunol Rev. 2009 May;229(1):126-44. (PMID: 19426219)
      J Immunol. 2007 Dec 1;179(11):7305-15. (PMID: 18025173)
      Semin Cancer Biol. 2007 Aug;17(4):299-308. (PMID: 17656106)
      Int J Cancer. 1997 Nov 4;73(3):309-16. (PMID: 9359474)
      Nat Immunol. 2006 Nov;7(11):1166-73. (PMID: 17028589)
      J Immunol. 2008 Mar 1;180(5):3132-9. (PMID: 18292536)
      Blood. 2003 Apr 1;101(7):2620-7. (PMID: 12411307)
      Oncogene. 2010 Oct 21;29(42):5653-62. (PMID: 20729908)
      Immunity. 1994 Sep;1(6):447-56. (PMID: 7895156)
      Blood. 2001 Aug 15;98(4):1070-7. (PMID: 11493453)
      Nat Rev Immunol. 2009 Mar;9(3):162-74. (PMID: 19197294)
      Nat Immunol. 2004 Mar;5(3):255-65. (PMID: 14973438)
      Immunity. 2003 Apr;18(4):535-47. (PMID: 12705856)
      Cancer Immunol Immunother. 2011 Apr;60(4):537-46. (PMID: 21225259)
      J Exp Med. 2009 Apr 13;206(4):867-76. (PMID: 19307325)
      Immunity. 2001 Jan;14(1):13-20. (PMID: 11163226)
      Nat Med. 2004 Sep;10(9):942-9. (PMID: 15322536)
      J Exp Med. 2010 Mar 15;207(3):651-67. (PMID: 20156973)
      Cancer Res. 1999 Jul 1;59(13):3128-33. (PMID: 10397255)
      Nat Immunol. 2006 Nov;7(11):1174-81. (PMID: 17028587)
      J Immunol. 2009 Apr 15;182(8):4499-506. (PMID: 19342621)
      Nat Rev Immunol. 2010 Apr;10(4):248-56. (PMID: 20336152)
      J Exp Med. 2003 Aug 18;198(4):569-80. (PMID: 12925674)
      Nat Med. 1999 Jul;5(7):780-7. (PMID: 10395323)
      Annu Rev Immunol. 2007;25:267-96. (PMID: 17134371)
      J Exp Med. 2010 Mar 15;207(3):637-50. (PMID: 20156971)
      J Exp Med. 2005 Jan 17;201(2):181-7. (PMID: 15657288)
      Nat Immunol. 2005 May;6(5):472-80. (PMID: 15834410)
      Int J Cancer. 2010 Aug 15;127(4):759-67. (PMID: 20518016)
      Cell. 2002 Jun 14;109(6):719-31. (PMID: 12086671)
      J Immunol. 2008 Aug 1;181(3):1622-6. (PMID: 18641297)
      J Immunol. 2006 Feb 15;176(4):2279-91. (PMID: 16455984)
      Science. 1996 May 10;272(5263):892-5. (PMID: 8629027)
      Blood. 2007 Apr 1;109(7):2878-86. (PMID: 17148585)
      Science. 1996 Mar 22;271(5256):1734-6. (PMID: 8596936)
    • Grant Information:
      AI051519 United States AI NIAID NIH HHS; P30 AI051519 United States AI NIAID NIH HHS; AI059738 United States AI NIAID NIH HHS; R01 AI059738 United States AI NIAID NIH HHS; T32 GM007288 United States GM NIGMS NIH HHS; R56 AI059738 United States AI NIAID NIH HHS; GM007288 United States GM NIGMS NIH HHS
    • Accession Number:
      0 (NFATC Transcription Factors)
    • Publication Date:
      Date Created: 20120807 Date Completed: 20121128 Latest Revision: 20211021
    • Publication Date:
      20240829
    • Accession Number:
      PMC3445721
    • Accession Number:
      10.1158/0008-5472.CAN-11-3775
    • Accession Number:
      22865456