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[Enhanced antitumor effects induced by lymphotactin gene-modified dendritic cells after pulsed with tumor antigen
1Department of Immunology, Second Military Medical University, Shanghai 200433.
Objective:
To evaluate the potent effects of lymphotactin on tumor immunogene therapy and to improve the therapeutic efficacy of dendritic cells (DCs)-based vaccine, the protective and therapeutic effects of tumor antigen peptide-pulsed lymphotactin gene-modified dendritic cells were investigated.
Methods:
In the tumor model of 3LL Lewis lung carcinoma, mouse bone marrow DCs transduced with mouse lymphotactin gene by adenovirus vector (Ltn-DC) were pulsed with MHC-I-restricted, 3LL cell-specific tumor peptide Mut 1 (FEQNTAQP), and used to vaccinate syngeneic mice or to treat the preestablished tumor-bearing mice with spontaneous pulmonary metastases.
Results:
Immunization with Mut 1 peptide-pulsed Ltn-DC induced specific CTL against 3LL cells and induced protective antitumor immunity, which rendered the immunized mice resistant completely to 3LL tumor challenge. In vivo depletion of immune cell subsets with mAbs demonstrated that the protective immunity induced by Mut1 peptide-pulsed Ltn-DC in the induction phase was dependent on both CD4+ T cells and CD8+ T cells rather than NK cells, and in the effector phase on CD8+ T cells rather than CD4+ T cells or NK cells. CD28/CTLA4 pathway of T cell costimulation and IFN-gamma were also necessary for induction of antitumor immunity by Ltn-DC pulsed with Mut1 peptide. Treatment with Mut1 peptide-pulsed Ltn-DC significantly inhibited the 3LL spontaneous pulmonary metastases of the preestablished tumor-bearing mice and exhibited obvious therapeutic effects.
Conclusions:
Our data suggest that Ltn gene modified DCs are more potent in the induction of protective and therapeutic antitumor immunity through the preferential chemotaxis of DCs on T cells. Vaccination with tumor antigen-pulsed Ltn-DC may be a novel approach to immunotherapy of cancer.