IL-4-transduced tumor cell vaccine induces immunoregulatory type 2 CD8 T lymphocytes that cure lung metastases upon adoptive transfer

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 polarizati on in both CD4 and CD8 T lymphocyte subsets. We focused on the antitumor ac tivity exerted by type 2 CD8(+) T cells (Tc2) activated by IL-4 tumor cell vaccination. Tc2 lymphocytes lacked in vitro tumor cytotoxicity, but releas ed IL-4 upon stimulation with tumor cells, as shown by limiting dilution an alysis of the frequencies of tumor-specific pCTL and of CD8 cells producing the cytokine. In vivo fresh purified CD8(+) T lymphocytes from IL-4-vaccin ated 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 antit umor effect of adoptively transferred Tc2 lymphocytes needed host CD8 T cel ls and AsGM1 leukocyte populations, and partially granulocytes. These data indicate that Tc2 CD8(+) T cells exert immunoregulatory functions and induc e tumor rejection through the cooperation of bystander lymphoid effector ce lls. Tumor eradication is thus not restricted to a type 1 response, but can also be mediated by a type 2 biased T cell response.