Infiltration of a mesothelioma by IFN-γ-producing cells and tumor rejection after depletion of regulatory T cells

Depletion of CD4(+)CD25(+)Foxp3(+) regulatory T cells (CD25(+) T-reg) with an anti-CD25 Ab results in immune-mediated rejection of tolerogenic solid tumors. In this study, we have examined the immune response to a mesothelioma tumor in mice after depletion of CD25(+) cells to elucidate the cellular mechanisms of CD25(+) T-reg, a subject over which there is currently much conjecture. Tumor rejection was found to be primarily due to the action of CD8(+) T cells, although CD4(+) cells appeared to play some role. Depletion of CD25(+) cells resulted in an accumulation in tumor tissue of CD4(+) and CD8(+) T cells and NK cells that were producing the potent antitumor cytokine IFN-gamma. Invasion of tumors by CD8(+) T cells was partially dependent on the presence of CD4(+) T cells. Although a significant increase in the proliferation and number of tumor-specific CD8(+) T cells was observed in lymph nodes draining the tumor of anti -CD25-treated mice, this effect was relatively modest compared with the large increase in IFN-gamma-producing T cells found in tumor tissue, which suggests that the migration of T cells into. tumor tissue may also have been altered. Depletion of CD25(+) cells did not appear to modulate antitumor CTL activity on a per cell basis. Our data suggests that CD25(+) T-reg limit the accumulation of activated T cells producing IFN-gamma in the tumor tissue and, to a lesser extent, activation and/or rate of mitosis of tumor-specific T cells in lymph nodes.