A therapeutic OX40 agonist dynamically alters dendritic, endothelial, and T cell subsets within the established tumor microenvironment.
Little preclinical modeling currently exists to support the use of OX40 agonists as therapeutic agents in the setting of advanced cancers, as well as the mechanisms through which therapeutic efficacy is achieved. We show that treatment of mice bearing well-established day 17 sarcomas with a novel OX40 ligand-Fc fusion protein (OX40L-Fc) resulted in tumor regression or dormancy in the majority of treated animals. Unexpectedly, dendritic cells (DC) in the progressive tumor microenvironment (TME) acquire OX40 expression and bind fluorescently labeled OX40L-Fc. Furthermore, longitudinal analyses revealed that DCs become enriched in the tumor-draining lymph node (TDLN) of both wild-type and Rag-/- mice within 3 days after OX40L-Fc treatment. By day 7 after treatment, a significant expansion of CXCR3+ T effector cells was noted in the TDLN, and by day 10 after treatment, type 1 polarized T cells exhibiting a reactivated memory phenotype had accumulated in the tumors. High levels of CXCL9 (a CXCR3 ligand) and enhanced expression of VCAM-1 by vascular endothelial cells (VEC) were observed in the TME early after treatment with OX40L-Fc. Notably, these vascular alterations were maintained in Rag-/- mice, indicating that the OX40L-Fc-mediated activation of both DC and VEC occurs in a T-cell-independent manner. Collectively, these findings support a paradigm in which the stimulation of DC, T cells, and the tumor vasculature by an OX40 agonist dynamically orchestrates the activation, expansion, and recruitment of therapeutic T cells into established tumors.
Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
Angela D
AD
Pardee
Dustin
D
McCurry
Sean
S
Alber
Peisheng
P
Hu
Alan L
AL
Epstein
Walter J
WJ
Storkus
D000818:Animals; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D042783:Endothelial Cells / Q000276:immunology* / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D007141:Immunoglobulin Fc Fragments / Q000235:genetics / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D019394:Ki-67 Antigen / Q000378:metabolism; D051379:Mice; D057507:Mice, 129 Strain; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D054400:Receptors, CCR7 / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D012513:Sarcoma, Experimental / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D059016:Tumor Microenvironment / Q000187:drug effects* / Q000276:immunology
C515371:Ccr7 protein, mouse; D007141:Immunoglobulin Fc Fragments; D019394:Ki-67 Antigen; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D054400:Receptors, CCR7; D011993:Recombinant Fusion Proteins