1. IL-4-transduced tumor cell vaccine induces immunoregulatory type 2 CD8 T lymphocytes that cure lung metastases upon adoptive transfer.
- Author
-
Rodolfo M, Zilocchi C, Accornero P, Cappetti B, Arioli I, and Colombo MP
- Subjects
- Animals, CD8-Positive T-Lymphocytes metabolism, CD8-Positive T-Lymphocytes transplantation, Cancer Vaccines genetics, Carrier Proteins genetics, Carrier Proteins immunology, Cell Communication immunology, Cytokines metabolism, Female, Folate Receptors, GPI-Anchored, Gene Transfer Techniques, Granulocytes immunology, Interleukin-4 genetics, Killer Cells, Natural immunology, Longevity, Lung Neoplasms immunology, Lymphocyte Activation genetics, Mice, Mice, Inbred BALB C, Mice, Knockout, Retroviridae genetics, T-Lymphocyte Subsets metabolism, T-Lymphocyte Subsets transplantation, Adoptive Transfer methods, CD8-Positive T-Lymphocytes immunology, Cancer Vaccines immunology, Interleukin-4 immunology, Lung Neoplasms secondary, Lung Neoplasms therapy, Lymphocyte Activation immunology, Receptors, Cell Surface, T-Lymphocyte Subsets immunology
- Abstract
Vaccinations with tumor cells engineered to produce IL-4 prolonged survival and cured 30% of mice bearing pulmonary metastases, an effect abrogated by in vivo depletion of T cells. Vaccination induced type 2 T cell polarization in both CD4 and CD8 T lymphocyte subsets. We focused on the antitumor activity exerted by type 2 CD8+ T cells (Tc2) activated by IL-4 tumor cell vaccination. Tc2 lymphocytes lacked in vitro tumor cytotoxicity, but released IL-4 upon stimulation with tumor cells, as shown by limiting dilution analysis of the frequencies of tumor-specific pCTL and of CD8 cells producing the cytokine. In vivo fresh purified CD8+ T lymphocytes from IL-4-vaccinated mice eliminated 80-100% of lung metastases when transferred into tumor-bearing mice. CD8+ lymphocytes from IL-4-vaccinated IFN-gamma knockout (KO), but not from IL-4 KO, mice cured lung metastases, thus indicating that IL-4 produced by Tc2 cells was instrumental for tumor rejection. The antitumor effect of adoptively transferred Tc2 lymphocytes needed host CD8 T cells and AsGM1 leukocyte populations, and partially granulocytes. These data indicate that Tc2 CD8+ T cells exert immunoregulatory functions and induce tumor rejection through the cooperation of bystander lymphoid effector cells. Tumor eradication is thus not restricted to a type 1 response, but can also be mediated by a type 2 biased T cell response. more...
- Published
- 1999