New therapeutic approaches to treat cancer: efficacy of CIITA vaccination in Glioblastoma and Oral Cancer

The MHC Class II Transactivator (CIITA) is the major transcriptional coordinator of the major histocompatibility complex (MHC) class II (MHC-II) genes. Our previous studies demonstrated that CIITA-induced MHC-II expression in tumor cells of distinct histological origin renders these cells surrogate Antigen Presenting Cells (APCs) of their own tumor antigens. CIITA-positive tumors trigger tumor-specific MHC-II-restricted CD4+ T helper cells (Th), which are fundamental to both initiate all adaptive immune responses and maintain the proliferation and cytotoxic activity of CD8+ cytotoxic T cells (Tc), the terminal effectors of anti-tumor immunity. Here we extend our approach to Glioblastoma (GBM) and to Oral Squamous Cell Carcinoma (OSCC), which represent a serious challenge in clinical setting for their malignancy. We also began to investigate the possibility to use Adenoviral vectors expressing CIITA as a potent tool for tumor therapy. Our findings demonstrate that murine glioblastoma GL261-CIITA tumors are rejected or significantly reduced in their growth compared to GL261 tumors in vivo. Moreover, preimplantation of GL261-CIITA tumor cells in one brain hemisphere results in complete rejection or strong growth retardation of GL261 tumor cells in the opposite hemisphere. Similar results were obtained for OSCC tumors, indeed murine OSCC MOC2-CIITA tumor cells are rejected or strongly retarded in their growth in vivo. When challenged with MOC2 parental tumor cells (MOC2-pc), these animals rejected tumor growth, indicating the acquisition of an anamnestic response. Adoptive cell transfer (ACT) experiments showed that total immune spleen cells from tumor-protected mice, as well as purified CD8+ and, more importantly, CD4+ T lymphocytes significantly protected from MOC2-pc tumor take, demonstrating the ability of CIITA-transfected tumor cells to promote a long-lasting anti-tumor immune response triggered by both Th and Tc lymphocytes. Finally, preliminary results showed that intratumor injection of Ad-CIITA viral vectors significantly retard parental tumor growth in vivo. These results validate our vaccination approach in GBM and OSCC and suggest the efficacy of Ad-CIITA viral vectors strategy in tumor therapy paving the way for more detailed and larger studies with, in conjunction with adjuvant vaccination with MHC-II-bound specific tumor antigens, will constitute a valuable alternative to treat human cancer.