This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Serafini, P. Articles by Borrello, I. Search for Related Content PubMed PubMed Citation Articles by Serafini, P. Articles by Borrello, I.

High-Dose Granulocyte-Macrophage Colony-Stimulating Factor-Producing Vaccines Impair the Immune Response through the Recruitment of Myeloid Suppressor Cells

¹ Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland; and ² Department of Oncology and Surgical Sciences, Padova, Italy

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.

This article has been cited by other articles:

				P. A. Cohen, G. K. Koski, B. J. Czerniecki, K. D. Bunting, X.-Y. Fu, Z. Wang, W.-J. Zhang, C. S. Carter, M. Awad, C. A. Distel, et al. STAT3- and STAT5-dependent pathways competitively regulate the pan-differentiation of CD34pos cells into tumor-competent dendritic cells Blood, September 1, 2008; 112(5): 1832 - 1843. [Abstract] [Full Text] [PDF]

				A. I. Daud, N. Mirza, B. Lenox, S. Andrews, P. Urbas, G. X. Gao, J.-H. Lee, V. K. Sondak, A. I. Riker, R. C. DeConti, et al. Phenotypic and Functional Analysis of Dendritic Cells and Clinical Outcome in Patients With High-Risk Melanoma Treated With Adjuvant Granulocyte Macrophage Colony-Stimulating Factor J. Clin. Oncol., July 1, 2008; 26(19): 3235 - 3241. [Abstract] [Full Text] [PDF]

				V. S. Zimmermann, A. Casati, C. Schiering, S. Caserta, R. Hess Michelini, V. Basso, and A. Mondino Tumors Hamper the Immunogenic Competence of CD4+ T Cell-Directed Dendritic Cell Vaccination J. Immunol., September 1, 2007; 179(5): 2899 - 2909. [Abstract] [Full Text] [PDF]

				P. Filipazzi, R. Valenti, V. Huber, L. Pilla, P. Canese, M. Iero, C. Castelli, L. Mariani, G. Parmiani, and L. Rivoltini Identification of a New Subset of Myeloid Suppressor Cells in Peripheral Blood of Melanoma Patients With Modulation by a Granulocyte-Macrophage Colony-Stimulation Factor-Based Antitumor Vaccine J. Clin. Oncol., June 20, 2007; 25(18): 2546 - 2553. [Abstract] [Full Text] [PDF]

				G Parmiani, C Castelli, L Pilla, M Santinami, M. Colombo, and L Rivoltini Opposite immune functions of GM-CSF administered as vaccine adjuvant in cancer patients Ann. Onc., February 1, 2007; 18(2): 226 - 232. [Abstract] [Full Text] [PDF]

				A. Jewett, C. Head, and N.A. Cacalano Emerging Mechanisms of Immunosuppression in Oral Cancers. J. Dent. Res., December 1, 2006; 85(12): 1061 - 1073. [Abstract] [Full Text] [PDF]

				Y. Nefedova, S. Nagaraj, A. Rosenbauer, C. Muro-Cacho, S. M. Sebti, and D. I. Gabrilovich Regulation of Dendritic Cell Differentiation and Antitumor Immune Response in Cancer by Pharmacologic-Selective Inhibition of the Janus-Activated Kinase 2/Signal Transducers and Activators of Transcription 3 Pathway Cancer Res., October 15, 2005; 65(20): 9525 - 9535. [Abstract] [Full Text] [PDF]