Importance of IL-10 for CTLA-4-mediated inhibition of tumor-eradicating immunity.
In this study, we show that engagement of CTLA-4 on tumor-infiltrating lymphocytes from low-dose melphalan (L-phenylalanine mustard (L-PAM))-treated MOPC-315 tumor bearers led to IL-10 secretion. In addition, the inhibitory activity of CTLA-4 ligation for IFN-gamma secretion following stimulation with anti-CD3 plus anti-CD28 mAb depended on IL-10 production. Consistent with the importance of IL-10 for CTLA-4-mediated inhibition, administration of neutralizing anti-IL-10 mAb to low-dose L-PAM-treated MOPC-315 tumor bearers (administration of blocking anti-CTLA-4 mAb) resulted in enhanced tumor-infiltrating lymphocyte-mediated anti-MOPC-315 cytotoxicity and led to complete tumor eradication in a higher percentage of mice than that observed with low-dose L-PAM alone. The percentage of MOPC-315 tumor-bearing mice cured following administration of neutralizing anti-IL-10 mAb to low-dose L-PAM-treated MOPC-315 tumor bearers was comparable to that observed following administration of blocking anti-CTLA-4 mAb. Moreover, IL-10 neutralization together with CTLA-4 blockade did not provide added therapeutic benefits to low-dose L-PAM-treated MOPC-315 tumor bearers. Taken together, these results indicate that CTLA-4 blockade improves the therapeutic outcome of low-dose L-PAM for MOPC-315 tumor bearers by inhibiting IL-10 secretion as a consequence of blocking CTLA-4 ligation.
Jovasevic
Vladimir M
VM
Department of Biochemistry and Molecular Genetics, University of Illinois, Chicago, IL 60612, USA.
Gorelik
Leonid
L
Bluestone
Jeffrey A
JA
Mokyr
Margalit B
MB
D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D060908:CTLA-4 Antigen; D045744:Cell Line, Tumor; D004306:Dose-Response Relationship, Immunologic; D015536:Down-Regulation / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism; D008558:Melphalan / Q000008:administration & dosage; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D010954:Plasmacytoma / Q000276:immunology* / Q000517:prevention & control*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology
D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D007166:Immunosuppressive Agents; D016753:Interleukin-10; D007371:Interferon-gamma; D008558:Melphalan