The Combination of Ionizing Radiation and Peripheral Vaccination Produces Long-term Survival of Mice Bearing Established Invasive GL261Gliomas

Abstract Purpose:High-grade glioma treatment includes ionizing radiation therapy.The high invasiveness of glioma cells precludes their eradication and is responsible for the dismal prognosis. Recently, we reported the down-regulation of MHC class I (MHC-I) products in invading tumor cells in human and mouse GL261gliomas. Here, we tested the hypothesis that whole-brain radiotherapy (WBRT) up-regulates MHC-I expression on GL261 tumors and enhances the effectiveness of immunotherapy. Experimental Design:MHC-I molecule expression on GL261cells was analyzed in vitro and in vivo by flow cytometry and immunohistochemistry, respectively. To test the response of establishedGL261gliomas to treatment, micewithmeasurable (at CT imaging) brain tumorswere randomly assigned to four groups receiving (a) no treatment, (b) WBRT in two fractions of 4 Gy, (c) vaccinationwith irradiated GL261cells secreting granulocyte-macrophage colony-stimulating factor, or (d) WBRTand vaccination. Endpoints were tumor response and survival. Results: An ionizing radiation dose of 4 Gy maximally up-regulatedMHC-Imolecules on GL261 cells in vitro. In vivo,WBRT induced the expression of the h2-microglobulin light chain subunit of the MHC class I complex on glioma cells invading normal brain and increased CD4+ and CD8