We previously demonstrated the generation of a CD4 T cell-specific long lasting anti-tumor immune response in the H-2d BALB/c mouse model by using tumor cells that have been genetically modified with CIITA to express MHC-II I-E and I-A molecules. We have now investigated the pertinence of this approach in the H-2b C57BL/6 mouse model despite the defect in their I-Eα gene and thus the lack of expression of I-E subset. To this purpose we injected in vivo the CIITA-driven I-A-only MHC-II-positive LLC (lewis Lung Carcinoma) and MC38 colon carcinoma in the C57BL/6 mice and their growth rate along with the recipient's immune response were analyzed. The CIITA-transfected, MHC-II-positive tumor cells were either completely rejected or showed a significant growth retardation compared to the MHC-II-negative parental tumor. The protected mice were re-injected with the parental tumors and a complete rejection was obtained proving that a specific long lasting immune response was triggered by the CIITA-transfected tumors. Furthermore, total splenocytes or purified CD4+, CD8+ T cells and B cells were transferred from the vaccinated recipients to naïve recipients that were co-injected with the parental tumor cells and the results showed that CD4+ TH cells were the main effectors of the immune response against the tumor cells. Interestingly, similar results were obtained in C57BL/6-DOG transgenic mice whose dendritic cells could be conditionally ablated after administration of Diphteria toxin. These results demonstrate the validity of triggering a specific, long-lasting anti-tumor immune response using CIITA-driven MHC class II positive tumor cells of different MHC haplotype as stimulators. Importantly, the results establish that expression of a single MHC-II restriction element, I-A, in tumor cells is sufficient to trigger CD4+ TH cell protective immune response, strongly suggesting that the relevant tumor-associated antigenic repertoire can be displayed without the need of the I-E restriction element. Finally, these results strongly suggest that CIITA-modified tumor cells can act as antigen presenting cells in vivo to prime naïve CD4+ TH cells against tumor antigens. Abstract nr A014.