Therapeutic efficacy of OX-40 receptor antibody depends on tumor immunogenicity and anatomic site of tumor growth

The OX-40 receptor (OX-40R) is a cell surface glycoprotein of the tumor nec rosis factor receptor family that is expressed primarily on activated CD4 T cells, Engagement of OX-40R by the OX-40 ligand (OX-40L) is known to costi mulate the production of cytokines by activated T lymphocytes and to rescue effector T cells from activation-induced cell death, It was previously rep orted that in vivo ligation of OX-40R by administration of OX-40L:immunoglo bulin fusion protein or OX-40R monoclonal antibody (mAb) resulted in a sign ificant prolongation of survival of tumor-bearing mice in four histological ly distinct solid tumors, In this study, we demonstrate that the therapeuti c efficacy of OX-40R mAb was influenced by the tumor burden, the intrinsic immunogenicity of the tumor as well as by the histological site of tumor gr owth. Whereas subdermal and intracranial growth of weakly immunogenic MCA 2 03 and MCA 205 sarcomas and GL261 glioma were susceptible to the mAb treatm ent, established pulmonary MCA 205 metastases were refractory to the same r egimen of treatment. Furthermore, the mAb administration had no impact on t he growth of the poorly immunogenic B16/D5 melanoma, Tumor regression media ted by OX-40R mAb was dependent on the participation of both CD4 and CD8 T cells and as a result of tumor rejection, a long-term tumor-specific immuni ty was established. Analysis of tumor-infiltrating T cells revealed the pre sence of a far greater number of OX-40R(+) T cells of both CD4 and CDS phen otypes in the intracranial immunogenic GL261 glioma than that in the poorly immunogenic: B16/D5 melanoma, These results suggest that ligation of OX-40 R on activated T cells in situ in the tumor may provide a necessary costimu latory signal to augment immune responses leading to tumor regression and i mmunological memory.