High-dose granulocyte-macrophage colony-stimulating factor-producing vaccines impair the immune response through the recruitment of myeloid suppressor cells
Tumor vaccines have shown promise in early clinical trials. Among them, tumor cells genetically engineered to secrete biologically active granulocyte-macrophage colony-stimulating factor (GM-CSF) can generate a systemic antitumor immune response. Although the minimal required GM-CSF dose produced by...
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Published in | Cancer research (Chicago, Ill.) Vol. 64; no. 17; pp. 6337 - 6343 |
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Main Authors | , , , , , |
Format | Journal Article |
Language | English |
Published |
Philadelphia, PA
American Association for Cancer Research
01.09.2004
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Subjects | |
Online Access | Get full text |
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Abstract | Tumor vaccines have shown promise in early clinical trials. Among them, tumor cells genetically engineered to secrete biologically active granulocyte-macrophage colony-stimulating factor (GM-CSF) can generate a systemic antitumor immune response. Although the minimal required GM-CSF dose produced by modified tumor cells to achieve a measurable antitumor effect is well known, no data examined whether an upper therapeutic limit may exist for this vaccination strategy. Because recent data demonstrate an immunosuppressive effect of GM-CSF produced by growing tumors, we thus sought to determine whether high GM-CSF doses administered in a vaccine formulation could impair antitumor immunity. Using a vaccine strategy involving a GM-CSF-producing bystander cell line (B78H1-GM) admixed with autologous tumor, we assessed the impact of varying doses of GM-CSF while maintaining a constant antigen dose. Our results defined a threshold above which a GM-CSF-based vaccine not only lost its efficacy, but more importantly for its clinical implications resulted in substantial immunosuppression in vivo. Above this threshold, GM-CSF induced Gr1+/CD11b+ myeloid suppressor cells that substantially impaired antigen-specific T-cell responses and adversely affected antitumor immune responses in vivo. The dual effects of GM-CSF are mediated by the systemic and not local concentration of this cytokine. Myeloid suppressor cell-induced immunosuppression is mediated by nitric oxide production via inducible nitric oxide synthase (iNOS) because the specific iNOS inhibitor, l-NMMA, restored antigen-specific T-cell responsiveness in vitro. Taken together, our data demonstrated the negative impact of supra-therapeutic vaccine doses of GM-CSF and underscored the importance of identifying these critical variables in an effort to increase the therapeutic efficacy of tumor vaccines. |
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AbstractList | Tumor vaccines have shown promise in early clinical trials. Among them, tumor cells genetically engineered to secrete biologically active granulocyte-macrophage colony-stimulating factor (GM-CSF) can generate a systemic antitumor immune response. Although the minimal required GM-CSF dose produced by modified tumor cells to achieve a measurable antitumor effect is well known, no data examined whether an upper therapeutic limit may exist for this vaccination strategy. Because recent data demonstrate an immunosuppressive effect of GM-CSF produced by growing tumors, we thus sought to determine whether high GM-CSF doses administered in a vaccine formulation could impair antitumor immunity. Using a vaccine strategy involving a GM-CSF-producing bystander cell line (B78H1-GM) admixed with autologous tumor, we assessed the impact of varying doses of GM-CSF while maintaining a constant antigen dose. Our results defined a threshold above which a GM-CSF-based vaccine not only lost its efficacy, but more importantly for its clinical implications resulted in substantial immunosuppression in vivo. Above this threshold, GM-CSF induced Gr1+/CD11b+ myeloid suppressor cells that substantially impaired antigen-specific T-cell responses and adversely affected antitumor immune responses in vivo. The dual effects of GM-CSF are mediated by the systemic and not local concentration of this cytokine. Myeloid suppressor cell-induced immunosuppression is mediated by nitric oxide production via inducible nitric oxide synthase (iNOS) because the specific iNOS inhibitor, l-NMMA, restored antigen-specific T-cell responsiveness in vitro. Taken together, our data demonstrated the negative impact of supra-therapeutic vaccine doses of GM-CSF and underscored the importance of identifying these critical variables in an effort to increase the therapeutic efficacy of tumor vaccines. Tumor vaccines have shown promise in early clinical trials. Among them, tumor cells genetically engineered to secrete biologically active granulocyte- macrophage colony-stimulating factor (GM-CSF) can generate a systemic antitumor immune response. Although the minimal required GM-CSF dose produced by modified tumor cells to achieve a measurable antitumor effect is well known, no data examined whether an upper therapeutic limit may exist for this vaccination strategy. Because recent data demonstrate an immunosuppressive effect of GM-CSF produced by growing tumors, we thus sought to determine whether high GM-CSF doses administered in a vaccine formulation could impair antitumor immunity. Using a vaccine strategy involving a GM-CSF-producing bystander cell line (B78H1-GM) admixed with autologous tumor, we assessed the impact of varying doses of GM-CSF while maintaining a constant antigen dose. Our results defined a threshold above which a GM-CSF-based vaccine not only lost its efficacy, but more importantly for its clinical implications resulted in substantial immunosuppression in vivo. Above this threshold, GM-CSF induced Gr1 super(+)/CD11b super(+) myeloid suppressor cells that substantially impaired antigen-specific T-cell responses and adversely affected antitumor immune responses in vivo. The dual effects of GM-CSF are mediated by the systemic and not local concentration of this cytokine. Myeloid suppressor cell-induced immunosuppression is mediated by nitric oxide production via inducible nitric oxide synthase (iNOS) because the specific iNOS inhibitor, L-NMMA, restored antigen-specific T-cell responsiveness in vitro. Taken together, our data demonstrated the negative impact of supra-therapeutic vaccine doses of GM-CSF and underscored the importance of identifying these critical variables in an effort to increase the therapeutic efficacy of tumor vaccines. |
Author | CARBLEY, Rebecca TAN, Gladys NOONAN, Kimberly A BRONTE, Vincenzo SERAFINI, Paolo BORRELLO, Ivan |
Author_xml | – sequence: 1 givenname: Paolo surname: SERAFINI fullname: SERAFINI, Paolo organization: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, United States – sequence: 2 givenname: Rebecca surname: CARBLEY fullname: CARBLEY, Rebecca organization: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, United States – sequence: 3 givenname: Kimberly A surname: NOONAN fullname: NOONAN, Kimberly A organization: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, United States – sequence: 4 givenname: Gladys surname: TAN fullname: TAN, Gladys organization: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, United States – sequence: 5 givenname: Vincenzo surname: BRONTE fullname: BRONTE, Vincenzo organization: Department of Oncology and Surgical Sciences, Padova, Italy – sequence: 6 givenname: Ivan surname: BORRELLO fullname: BORRELLO, Ivan organization: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, United States |
BackLink | http://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=16084213$$DView record in Pascal Francis https://www.ncbi.nlm.nih.gov/pubmed/15342423$$D View this record in MEDLINE/PubMed |
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Snippet | Tumor vaccines have shown promise in early clinical trials. Among them, tumor cells genetically engineered to secrete biologically active... Tumor vaccines have shown promise in early clinical trials. Among them, tumor cells genetically engineered to secrete biologically active granulocyte-... |
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SubjectTerms | Animals Antineoplastic agents Biological and medical sciences Cancer Vaccines - adverse effects Cancer Vaccines - immunology CD4-Positive T-Lymphocytes - immunology Cell Line, Tumor Dose-Response Relationship, Immunologic Female Granulocyte-Macrophage Colony-Stimulating Factor - adverse effects Granulocyte-Macrophage Colony-Stimulating Factor - immunology Male Medical sciences Mice Mice, Inbred BALB C Mice, Transgenic Myeloid Cells - immunology Neoplasms, Experimental - immunology Neoplasms, Experimental - therapy Pharmacology. Drug treatments Tumors |
Title | High-dose granulocyte-macrophage colony-stimulating factor-producing vaccines impair the immune response through the recruitment of myeloid suppressor cells |
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