Tumor rejection effects of allo-restricted tumor peptide-specific CD4⁺ T cells on human cervical cancer cell xenograft in nude mice.
ABSTRACT Generation of tumor specific allo-reactive CD4⁺ T cells is important to circumvent tumor tolerance. Here, we generate allo-restricted peptide-specific CD4⁺ T cells by co-culture of lymphocytes and autologous monocytes bearing allogeneic HLA-DR15 molecule associated with its restricted peptide. Binding of a dimeric HLA-DR15/IgG1-Fc fusion protein (the dimer) to HLA-DR15 negative (HLA-DR15-ve) monocytes made the monocytes coated with the allogeneic epitope. An increased proliferation of CD4⁺ T cells and induction of Th1 cells appeared after co-culturing of HLA-DR15-ve lymphocytes and the autologous monocytes loaded with the dimer. The co-cultural bulks showed an increased frequency of the specific dimer-stained CD4⁺ T cells and the expanded CD4⁺ T cells exhibited an elevated IFN-γ production in response to specific TCR ligand. Tumor rejection effects of the allo-restricted E7-specific CD4⁺ T cells raised by the coculture were observed in nude mice challenged with human cervical cancer cell SiHa expressing both HLA-DR15 and E7 antigens, as the tumor avoidance and lifespan of the mice were improved after adoptive transfer of the CD4⁺ T cells. This study may help to develop strategies to separate graft-versus-leukemia or graft-versus-tumor reaction from graft-versus-host disease, and add to the pool of human high-avidity TCRs specific for tumor or virus antigens.