IMMUNOGLOBULIN Fc FRAGMENT TAGGING ACTIVATION OF ENDOGENOUS CD4 AND CD8 T CELLS AND ENHANCEMENT OF ANTITUMOR EFFECTS OF LENTIVECTOR IMMUNIZATION

摘要

A lentivector has been engineered to express a fusion antigen composed of hepatitis B surface protein (HBsAg) and IgG2a Fc fragment (HBS-Fc-Iv) to increase both the magnitude of CD8 response and to induce effective co-activation of CD4 T cells. Immunization with this HBS-Fc-Iv caused significant regression of established tumors. Immunological analysis revealed that, compared to HBS-Iv without the Fc fragment, immunization with HBS-Fc-Iv markedly increased the number of functional CD8 and CD4 T cells and the level of Th1/Tc1-like cytokines in the tumor, while substantially decreasing the Treg ratio. The favorable immunologic changes in tumor lesions and the improvement of antitumor effects from HBS-Fc-Iv immunization were dependent on the CD4 activation, which was Fc receptor mediated. Adoptive transfer of the CD4 T cells from the HBS-Fc-Iv immunized mice could activate endogenous CD8 T cells in an IFNγ-dependent manner. Endogenous CD4 T cells can be activated by lentivirus expressing Fc-tagged antigen to provide another layer of help, i.e., creating a Th1/Tc1 like pro-inflammatory milieu within the tumor lesion to help the effector phase of immune responses to enhance the antitumor effect.