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-γ. 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-γ-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-γ in the tumor tissue and, to a lesser extent, activation and/or rate of mitosis of tumor-specific T cells in lymph nodes.