Provision of granulocyte-macrophage colony-stimulating factor converts an autoimmune response to a self-antigen into an antitumor response.
Many tumor Ags recognized by T cells are self-Ags. Because high avidity, self-reactive T cells are deleted in the thymus, any residual self-reactive T cells existing in the periphery are likely to be low avidity and nonresponsive due to peripheral tolerance mechanisms. Activation of these residual T cells is critical for targeting tumors for immunotherapy. In this study, we studied immune responses against the murine B16 melanoma using a tyrosinase-related protein 2 (TRP-2) peptide as a model tumor/self-Ag. Our results showed that TRP-2 peptide vaccination alone elicited a weak T cell response and modestly decreased B16 lung tumor nodules. The combination of peptide vaccination and treatment with an Ab directed against the inhibitory receptor CTLA-4 enhanced the immune response against TRP-2 peptide, inducing autoimmune depigmentation and further decreasing lung tumor nodules. However, both vaccination methods failed to protect against orthotopic (s.c.) B16 tumor challenge. The addition of an irradiated GM-CSF-expressing, amelanotic tumor cell vaccine significantly delayed s.c. B16 tumor growth. Subsequent studies revealed that provision of GM-CSF increased dendritic cell numbers in lymph nodes and spleen. Furthermore, addition of CTLA-4 blockade increased the frequency of TRP-2-specific, IFN-secreting T cells in spleen and lymph nodes. Overall, our results indicate that combining enhancement of Ag presentation with removal of CTLA-4-mediated inhibition can convert a "weaker" autoimmune response into a more potent antitumor immune response.
Ji
Qingyong
Q
Tumor Immunity and Tolerance Section, Laboratory of Molecular Immunoregulation, National Cancer Institute, Frederick Cancer Research and Development Center, Frederick, MD 21702, USA.
Gondek
David
D
Hurwitz
Arthur A
AA
D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage / Q000627:therapeutic use; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology; D000951:Antigens, Neoplasm / Q000008:administration & dosage / Q000276:immunology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000276:immunology / Q000627:therapeutic use; D001324:Autoantigens / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology; D060908:CTLA-4 Antigen; D019496:Cancer Vaccines / Q000008:administration & dosage; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000201:enzymology / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage / Q000502:physiology*; D017496:Hypopigmentation / Q000201:enzymology / Q000276:immunology; D007279:Injections, Subcutaneous; D019746:Intramolecular Oxidoreductases / Q000008:administration & dosage / Q000276:immunology; D008175:Lung Neoplasms / Q000276:immunology / Q000517:prevention & control / Q000556:secondary; D008546:Melanoma, Experimental / Q000201:enzymology / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D008565:Membrane Proteins / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology
D019138:Antibodies, Blocking; D015703:Antigens, CD; D000943:Antigens, Differentiation; D000951:Antigens, Neoplasm; D001324:Autoantigens; D060908:CTLA-4 Antigen; D019496:Cancer Vaccines; C556707:Ctla4 protein, mouse; D018984:Epitopes, T-Lymphocyte; D008565:Membrane Proteins; D010446:Peptide Fragments; C113139:Trp2 protein, vertebrate; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D019746:Intramolecular Oxidoreductases; C042501:dopachrome isomerase