دورية أكاديمية
Rescue of Tolerant CD8+ T Cells during Cancer Immunotherapy with IL2:Antibody Complexes.
العنوان: | Rescue of Tolerant CD8+ T Cells during Cancer Immunotherapy with IL2:Antibody Complexes. |
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المؤلفون: | Klevorn LE; Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri., Berrien-Elliott MM; Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri., Yuan J; Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri., Kuehm LM; Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri., Felock GD; Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri., Crowe SA; Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri., Teague RM; Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri. rteague@slu.edu.; Alvin J. Siteman NCI Comprehensive Cancer Center, St. Louis, Missouri. |
المصدر: | Cancer immunology research [Cancer Immunol Res] 2016 Dec; Vol. 4 (12), pp. 1016-1026. Date of Electronic Publication: 2016 Nov 01. |
نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural |
اللغة: | English |
بيانات الدورية: | Publisher: American Association for Cancer Research Country of Publication: United States NLM ID: 101614637 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2326-6074 (Electronic) Linking ISSN: 23266066 NLM ISO Abbreviation: Cancer Immunol Res Subsets: MEDLINE |
أسماء مطبوعة: | Original Publication: Philadelphia, PA : American Association for Cancer Research, [2013]- |
مواضيع طبية MeSH: | Immunotherapy*, Antibodies/*immunology , CD8-Positive T-Lymphocytes/*immunology , Interleukin-2/*immunology , Neoplasms/*therapy, Animals ; Cell Line, Tumor ; Humans ; Immune Tolerance ; Mice, Transgenic ; Neoplasms/immunology ; Receptors, Antigen, T-Cell/genetics |
مستخلص: | Interleukin-2 (IL2) was among the earliest reagents used for cancer immunotherapy due to its ability to support the survival and function of tumor-reactive T cells. However, treatment with IL2 is accompanied by off-target toxicity and low response rates in patients. In mouse models, these issues are largely overcome when IL2 is administered as a cytokine/antibody complex (IL2c). The complex has a longer serum half-life and can be designed for preferential cytokine delivery to specific cells of interest. Early studies showed IL2c could boost antitumor immunity in mice by activating tumor-reactive CD8 + T cells. But such functional T cells are often limited in the tumor microenvironment, where instead unresponsive tolerant T cells are eventually eliminated by apoptosis, representing a major obstacle to the success of cancer immunotherapy. We found that IL2c treatment rescued tumor-specific CD8 + T cells from a state of established tolerance, providing effective immunotherapy in tumor-bearing mice. Expression of the transcription factor T-bet was necessary to drive intratumoral IFNγ production and effector activity by T cells rescued with IL2c. Furthermore, IL2c promoted T-bet expression in human CD4 + and CD8 + T cells in humanized tumor-bearing mice, but also increased the frequency of Foxp3 + regulatory T cells. Our study reveals a novel role for IL2c as a powerful immunotherapeutic reagent capable of reversing tolerance in tumor-reactive T cells, and provides the first evidence that IL2c influences human T cells in vivo, highlighting the translational potential to modulate human antitumor immune responses. Cancer Immunol Res; 4(12); 1016-26. ©2016 AACR. Competing Interests: COI: The authors declare no potential conflicts of interest. (©2016 American Association for Cancer Research.) |
References: | Science. 2006 Mar 31;311(5769):1924-7. (PMID: 16484453) J Immunol. 2008 May 1;180(9):5789-93. (PMID: 18424696) Science. 2002 Jan 11;295(5553):338-42. (PMID: 11786644) J Immunol. 2009 Oct 15;183(8):4904-12. (PMID: 19801515) Proc Natl Acad Sci U S A. 2005 Jan 11;102(2):419-24. (PMID: 15623559) Proc Natl Acad Sci U S A. 2010 Jun 29;107(26):11906-11. (PMID: 20547866) Nat Immunol. 2011 Jun 20;12(7):597-606. (PMID: 21685955) JAMA. 1994 Mar 23-30;271(12):907-13. (PMID: 8120958) Nat Rev Immunol. 2012 Feb 17;12(3):180-90. (PMID: 22343569) Proc Natl Acad Sci U S A. 2003 Dec 23;100(26):15818-23. (PMID: 14673093) J Immunol. 2015 Nov 1;195(9):4537-44. (PMID: 26408669) Cancer Immunol Immunother. 1999 Jan;47(5):243-8. (PMID: 10022467) J Leukoc Biol. 2014 Sep;96(3):397-410. (PMID: 24823810) Cancer Res. 2013 Jan 15;73(2):605-16. (PMID: 23188506) Immunity. 2012 Oct 19;37(4):660-73. (PMID: 23041064) Science. 2003 Nov 7;302(5647):1041-3. (PMID: 14605368) J Immunol. 2001 Feb 15;166(4):2863-70. (PMID: 11160355) Immunity. 2015 May 19;42(5):815-25. (PMID: 25992858) Cancer. 1998 Aug 15;83(4):797-805. (PMID: 9708948) Proc Natl Acad Sci U S A. 2010 Feb 2;107(5):2171-6. (PMID: 20133862) Curr Protoc Immunol. 2008 May;Chapter 15:Unit 15.21. (PMID: 18491294) Science. 2012 Feb 10;335(6069):723-7. (PMID: 22267581) J Immunol. 2007 Jun 1;178(11):6849-60. (PMID: 17513733) J Immunol. 2014 Jun 15;192(12):5451-8. (PMID: 24907378) Proc Natl Acad Sci U S A. 2008 Oct 28;105(43):16683-8. (PMID: 18936481) Immunotherapy. 2014;6(7):833-52. (PMID: 25290416) J Exp Med. 2002 Jun 3;195(11):1407-18. (PMID: 12045239) Trends Immunol. 2014 Feb;35(2):51-60. (PMID: 24210163) Nat Med. 2006 Mar;12(3):335-41. (PMID: 16474399) Immunity. 2008 May;28(5):662-74. (PMID: 18424189) Immunol Lett. 2014 May-Jun;159(1-2):1-10. (PMID: 24512738) Trends Immunol. 2013 Jan;34(1):33-40. (PMID: 22999714) J Immunol. 1983 May;130(5):2203-8. (PMID: 6601147) J Immunol. 2008 Apr 15;180(8):5275-82. (PMID: 18390708) Proc Natl Acad Sci U S A. 2006 Jun 13;103(24):9166-71. (PMID: 16757567) Cancer Immunol Res. 2015 Feb;3(2):116-24. (PMID: 25516478) |
معلومات مُعتمدة: | R01 AI087764 United States AI NIAID NIH HHS; UL1 TR000448 United States TR NCATS NIH HHS |
المشرفين على المادة: | 0 (Antibodies) 0 (IL2 protein, human) 0 (Interleukin-2) 0 (Receptors, Antigen, T-Cell) |
تواريخ الأحداث: | Date Created: 20161103 Date Completed: 20171120 Latest Revision: 20181113 |
رمز التحديث: | 20231215 |
مُعرف محوري في PubMed: | PMC5135645 |
DOI: | 10.1158/2326-6066.CIR-16-0159 |
PMID: | 27803062 |
قاعدة البيانات: | MEDLINE |
تدمد: | 2326-6074 |
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DOI: | 10.1158/2326-6066.CIR-16-0159 |