Induction of anti-mammary cancer immunity by engaging the OX-40 receptor in vivo.
The OX-40 receptor (OX-40R) is a member of the tumor necrosis factor receptor (TNF-R) superfamily that is expressed on activated CD4+ T cells. The OX-40R is a costimulatory molecule that induces CD4+ T cell activation when engaged by its ligand (OX-40 L; found on antigen presenting cells). In human and murine tumors, we have shown upregulation of the OX-40R on CD4+ T cells from tumor-infiltrating lymphocytes (TIL) and tumor-draining lymph node cells (TDLNC) but not on systemic CD4+ T cells, such as peripheral blood lymphocytes (PBL) or splenocytes. In order to examine potentially heightened anti-tumor immunity through enhanced costimulation when engaging OX-40R in vivo, we inoculated mice with a murine mammary cancer cell line (SM1) and then treated with a soluble form of the OX-40 L. Mice injected with a lethal inoculum of SM1 cells were given two intraperitoneal injections (days 3 and 7 post-inoculation) of 100 microg soluble OX-40 L. Seven of 28 treated mice survived the lethal tumor inoculum, as compared to one of 28 control mice, demonstrating a significant survival benefit with treatment (p = 0.0136, log rank analysis). Mice that did not develop tumor by day 90 were rechallenged; all remained tumor-free. Mice were also injected with a second mammary tumor line (4T1) and treated with OX-40L:Ig with similar therapeutic results. Activation of OX-40R+ CD4+ T cells during mammary cancer priming stimulated an antitumor immune response resulting in enhanced survival and protective anti-tumor immunity. These results should have practical applications for treatment modalities for patients with breast cancer.
Morris
A
A
Department of Surgery, Oregon Health Sciences University, Portland, USA.
Vetto
J T
JT
Ramstad
T
T
Funatake
C J
CJ
Choolun
E
E
Entwisle
C
C
Weinberg
A D
AD
D000818:Animals; D006801:Humans; D007111:Immunity, Cellular; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008325:Mammary Neoplasms, Experimental / Q000276:immunology* / Q000401:mortality; D008562:Membrane Glycoproteins / Q000008:administration & dosage* / Q000276:immunology; D051379:Mice; D009363:Neoplasm Proteins / Q000276:immunology*; D053278:OX40 Ligand; D011971:Receptors, Immunologic / Q000276:immunology*; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000276:immunology*; D048069:Tumor Necrosis Factors
D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D053278:OX40 Ligand; D011971:Receptors, Immunologic; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor; C505716:TNFRSF4 protein, human; C089251:TNFSF4 protein, human; C505717:Tnfrsf4 protein, mouse; C504586:Tnfsf4 protein, mouse; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D048069:Tumor Necrosis Factors