A novel iNKT cell-mediated vaccine maneuver induces potent long-lasting anti-tumor immunity for advanced prostate cancer by boosting CD8+T cell memory and function (53.24)

Abstract

Abstract iNKT cells have considerable therapeutic promise in cancer, but so far this has not been fully realized. At issue has been delivering iNKT ligand and tumor Ag to the same APC for optimal processing and presentation. Also, although tumor-infiltrating APCs express CD1d in both prostate cancer (PCa) models and patients, tumor induced tolerance and suppression leads to defective iNKT activation. Whole-cell tumor vaccines represent a promising treatment approach and prevent tumor progression in multiple models of cancer. Here, we use an optimized approach consisting of alpha-galactosylceramide (aGalCer) and the GM-CSF-based PCa vaccine, ‘GVax’ combined with IL-12. This approach was capable of breaking tumor-induced tolerance and causing dramatic and substantial tumor regression and survival in large advanced prostate tumors in TRAMP mice. Remarkably, 10/12 vaccinated >9 month old mice rejected tumors, 'breaking tolerance', even at this late stage of tumor growth. The vaccine induced strong immune responses capable of reversing INKT defects in tumor-bearing mice as well as in patient iNKT in vitro. Both IL-12 and aGalCer were crucial for this response. Vaccinated mice had higher levels and activation of tumor-specific CD8 T, CD4 T and iNKT cells, and greater memory CD8 T cell expansion capable of producing the effector cytokines IFN-γ and TNF-α in response to tumor. These studies shed light on how whole cell vaccines targeting iNKTs can be utilized in PCa immunotherapy.