Adoptive immunotherapy as an in vivo model to explore antitumor mechanisms induced by a recombinant anticancer vaccine

We have described previously the construction, generation, and in vivo biologic consequences of a recombinant vaccinia virus containing the human CEA gene (rV-CEA) in an experimental murine colon carcinoma model. Immunization of C57BL/6 mice with rV-CEA led to antigen-specific inhibition of tumor growth in both prophylactic and therapeutic settings. Although such antitumor effects were correlated with the induction of CEA-specific T-cell responses, their exact contribution in the tumor rejection mechanism remained unclear. In this study, we examined the mechanism of action of rV-CEA, with emphasis on definition of the immune cells important for such antitumor effects. To that end, a cellular adoptive transfer model was established in vivo, which allowed specific functional analysis of donor-derived immune cells in naive, sublethally irradiated, tumor-bearing recipients, Splenocytes from rV-CEA-immunized donors expressed strong antitumor activity in such tumor-bearing recipients, whereas nonimmune donor cells did not. Depletion of immune T cells before cellular transfer abolished the antitumor response. Moreover, depletion of CD8(+) T cells before transfer resulted in the loss of antitumor activity, despite the presence of CD4(+) T cells, In contrast, antitumor activity was demonstrable with CD8-containing, CD4-depleted effecters, although it was not as effective as with both T-cell subpopulations combined, Finally, in beta(2)-microglobulin/CD8(+) T-cell-deficient mice, rV-CEA immunization exerted only partial antitumor protection, compared with the Immune-competent controls, Overall, we demonstrated that (a) antitumor activity induced by rV-CEA was essentially mediated by CD8(+) effectors; and (b) the combination of both CD8(+) and CD4(+) lymphocytes led to maximal antitumor therapeutic effects, suggesting an important helper or immunoregulatory contribution of the CD4(+) subset, Thus, adoptive cellular transfer strategies may have implications for both the study of recombinant anticancer vaccines and the development of potential clinical applications for cancer immunotherapy.