A therapeutic OX40 agonist dynamically alters dendritic, endothelial, and T cell subsets within the established tumor...

Area of Science:

• Immunology
• Oncology
• Cancer Research

Background:

• Limited preclinical models exist for OX40 agonists in advanced cancers.
• Mechanisms of therapeutic efficacy for OX40 agonists are not fully understood.

Purpose of the Study:

• To investigate the preclinical efficacy of a novel OX40 ligand-Fc fusion protein (OX40L-Fc) in established sarcomas.
• To elucidate the mechanisms of OX40 agonist-mediated anti-tumor immunity.

Main Methods:

• Treatment of mice with established sarcomas using OX40L-Fc.
• Analysis of dendritic cell (DC) phenotype and localization.
• Assessment of T cell activation, expansion, and phenotype in tumor-draining lymph nodes (TDLNs) and tumors.
• Evaluation of tumor microenvironment (TME) vascular changes and chemokine expression.

Main Results:

• OX40L-Fc treatment led to tumor regression or dormancy in most treated mice.
• Dendritic cells in the TME acquired OX40 expression and bound OX40L-Fc.
• DCs were enriched in TDLNs post-treatment, followed by expansion of CXCR3+ T effector cells.
• Type 1 polarized T cells with a reactivated memory phenotype accumulated in tumors.
• Increased CXCL9 and VCAM-1 expression by vascular endothelial cells were observed in the TME.
• Vascular alterations occurred independently of T cells, suggesting T-cell-independent DC and vascular activation.

Conclusions:

• OX40L-Fc demonstrates significant preclinical anti-tumor activity in established sarcomas.
• The study reveals a multi-faceted mechanism involving DC activation, T cell recruitment, and tumor vasculature modulation.
• OX40 agonists can orchestrate immune responses by stimulating DCs, T cells, and tumor vasculature for therapeutic benefit.