herapeutic OX40 Agonist Dynamically Alters Dendritic, othelial, and T Cell Subsets within the Established

Downlo le preclinical modeling currently exists to support the use of OX40 agonists as therapeutic agents in tting of advanced cancers, as well as the mechanisms through which therapeutic efficacy is achieved. ow that treatment of mice bearing well-established day 17 sarcomas with a novel OX40 ligand–Fc protein (OX40L-Fc) resulted in tumor regression or dormancy in the majority of treated animals. ectedly, dendritic cells (DC) in the progressive tumor microenvironment (TME) acquire OX40 expresnd bind fluorescently labeled OX40L-Fc. Furthermore, longitudinal analyses revealed that DCs become ed in the tumor-draining lymph node (TDLN) of both wild-type and Rag mice within 3 days after -Fc treatment. By day 7 after treatment, a significant expansion of CXCR3 T effector cells was noted TDLN, and by day 10 after treatment, type 1 polarized T cells exhibiting a reactivated memory phehad accumulated in the tumors. High levels of CXCL9 (a CXCR3 ligand) and enhanced expression of -1 by vascular endothelial cells (VEC) were observed in the TME early after treatment with OX40L-Fc. ly, these vascular alterations were maintained in Rag mice, indicating that the OX40L-Fc–mediated tion of both DC and VEC occurs in a T-cell–independent manner. Collectively, these findings support a gm in which the stimulation of DC, T cells, and the tumor vasculature by an OX40 agonist dynamically paradi orchestrates the activation, expansion, and recruitment of therapeutic T cells into established tumors. Cancer Res; 70(22); 9041–52. ©2010 AACR.