High-dose granulocyte-macrophage colony-stimulating factor-producing vaccines impair the immune response through the recruitment of myeloid suppressor cells

• Published in: Cancer research (Chicago, Ill.) Vol. 64; no. 17; pp. 6337 - 6343
• Main Authors: SERAFINI, Paolo, CARBLEY, Rebecca, NOONAN, Kimberly A, TAN, Gladys, BRONTE, Vincenzo, BORRELLO, Ivan
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.09.2004
• Subjects: 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; Immune response; Suppressor; Vaccine; Myeloid cell; High dose; Granulocyte macrophage colony stimulating factor; Recruitment
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-04-0757

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.