CIITA-induced MHC class II expression in tumor cells: a novel universal strategy of anti-tumor vaccination.

Priming and activation of CD4+ T helper (TH) cells against tumor associated antigens can be achieved after their recognition on antigen presenting cells (APC) only within the context of MHC class II (MHC-II) molecules. We previously reported successful triggering of TH-specific long lasting anti-tumor immune response in H-2d haplotype BALB/c mice using tumor cells genetically modified to express endogenous MHC-II genes (I-A and I-E) after transfection with CIITA (MHC-II transactivator). Now, we investigated the pertinence of this approach in H-2b haplotype C57BL/6 mice that only express I-A molecules due to a defect in their I-Eα gene. MC38 colon carcinoma cells of the H-2b haplotype were stably transfected with CIITA. Selected MHC-II positive clones were injected into C57BL/6 mice. Complete rejection or significant growth retardation as compared to MHC-II negative parental tumor was obtained. Subsequent challenge of the protected mice with parental tumor proved that the CIITA-transfected tumor engendered efficient anti-tumor vaccination. Then, adoptive cell transfer from the vaccinated mice to naïve recipients demonstrated that CD4+ TH cells orchestrate the anti-tumor protection. Finally, the use of CD11c.DTR transgenic mice in which conditional deletion of dendritic cells (DC) can be performed, and the use of Liposomal Clodronate as a depletion agent for macrophages, proved that CIITA-driven MHC-II positive tumor cells act as surrogate APC for priming and activating CD4+ TH cells, without the need of either DC or macrophages. These results demonstrate the validity of CIITA-driven MHC-II+ tumor cells as anti-tumor vaccination tool in mouse models of different haplotypes. Moreover, they prove that expression of a single MHC-II restriction element in tumor cells is sufficient to trigger anti-tumor CD4+ TH cells and, more importantly, demonstrate for the first time that CIITA-driven MHC-II expressing tumor cells can act as professional APCs in vivo to prime naïve tumor-specific CD4+ TH cells.