In pre-clinical tumor models, aOX40 therapy is often successful at treating small tumors but is less effective once the tumors become large. To cure large tumors it will likely require both an OX40 agonist to boost effector T cell function as well as inhibitors of T cell suppression. In this study, we show that combining aOX40 antibodies with an inhibitor of the TGF-B receptor (SM16) synergizes to elicit complete regression of large established MCA205 and CT-26 tumors. Evaluation of tumor-infiltrating T cells showed that SM16/aOX40 combination therapy resulted in an increase in proliferating granzyme B+ CD8 T cells, which produced higher levels of IFNg, compared to either agent alone. We also found that the dual treatment increased pSTAT3 expression in both CD4 and CD8 T cells isolated from tumors. Since others have published that STAT3 signaling is detrimental to T cell function within the tumor microenvironment we explored whether deletion of STAT3 in OX40-expressing cells would impact this potent combination therapy. Surprisingly, we found that deletion of STAT3 in OX40-expressing cells decreased the efficacy of this combination therapy, showing that the full therapeutic potential of this treatment depends on STAT3 signaling most likely in the T cells of tumor-bearing mice.
- Received October 1, 2014.
- Revision received January 12, 2015.
- Accepted January 13, 2015.
- Copyright © 2015, American Association for Cancer Research.