Combination immunotherapy of B16 melanoma using anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and granulocyte/macrophage colony-stimulating factor (GM-CSF)-producing vaccines induces rejection of subcutaneous and metastatic tumors accompanied by autoimmune depigmentation.
We examined the effectiveness of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) blockade, alone or in combination with a granulocyte/macrophage colony-stimulating factor (GM-CSF)-expressing tumor cell vaccine, on rejection of the highly tumorigenic, poorly immunogenic murine melanoma B16-BL6. Recently established tumors could be eradicated in 80% (68/85) of the cases using combination treatment, whereas each treatment by itself showed little or no effect. Tumor rejection was dependent on CD8(+) and NK1.1(+) cells but occurred irrespective of the presence of CD4(+) T cells. Mice surviving a primary challenge rejected a secondary challenge with B16-BL6 or the parental B16-F0 line. The same treatment regimen was found to be therapeutically effective against outgrowth of preestablished B16-F10 lung metastases, inducing long-term survival. Of all mice surviving B16-BL6 or B16-F10 tumors after combination treatment, 56% (38/68) developed depigmentation, starting at the site of vaccination or challenge and in most cases progressing to distant locations. Depigmentation was found to occur in CD4-depleted mice, strongly suggesting that the effect was mediated by CTLs. This study shows that CTLA-4 blockade provides a powerful tool to enhance T cell activation and memory against a poorly immunogenic spontaneous murine tumor and that this may involve recruitment of autoreactive T cells.
van Elsas
A
A
Howard Hughes Medical Institute, Cancer Research Laboratory, Department of Molecular and Cellular Biology, University of California, Berkeley 94720-3200, USA.
Hurwitz
A A
AA
Allison
J P
JP
D000069594:Abatacept; D000276:Adjuvants, Immunologic / Q000627:therapeutic use; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000941:Antigens / Q000276:immunology; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000096:biosynthesis* / Q000276:immunology; D000950:Antigens, Ly; D000954:Antigens, Surface; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000276:immunology* / Q000627:therapeutic use; D001327:Autoimmune Diseases / Q000276:immunology* / Q000628:therapy; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D060908:CTLA-4 Antigen; D019496:Cancer Vaccines / Q000276:immunology* / Q000627:therapeutic use; D002470:Cell Survival / Q000276:immunology; D005260:Female; D006084:Graft Rejection / Q000276:immunology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis* / Q000276:immunology; D006200:Hair Color / Q000276:immunology; D018796:Immunoconjugates; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007279:Injections, Subcutaneous; D037181:Lectins, C-Type; D008175:Lung Neoplasms / Q000276:immunology / Q000473:pathology / Q000556:secondary; D008213:Lymphocyte Activation; D008546:Melanoma, Experimental / Q000276:immunology* / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D055651:NK Cell Lectin-Like Receptor Subfamily B; D009368:Neoplasm Transplantation; D011506:Proteins / Q000276:immunology; D012880:Skin Pigmentation / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014820:Vitiligo / Q000276:immunology* / Q000473:pathology / Q000628:therapy
D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D000941:Antigens; D015703:Antigens, CD; D000943:Antigens, Differentiation; D000950:Antigens, Ly; D000954:Antigens, Surface; D060908:CTLA-4 Antigen; D019496:Cancer Vaccines; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; C527211:Klrb1c protein, mouse; D037181:Lectins, C-Type; D055651:NK Cell Lectin-Like Receptor Subfamily B; D011506:Proteins; D000069594:Abatacept; D016178:Granulocyte-Macrophage Colony-Stimulating Factor