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.) |
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| 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 |
|---|---|
| DOI: | 10.1158/2326-6066.CIR-16-0159 |