Cyclophosphamide-facilitated adoptive immunotherapy of an established tumor depends on elimination of tumor-induced suppressor T cells.

TLDR

Tumor‑induced T cell–mediated immunosuppression blocks adoptive immunotherapy of Meth A fibrosarcoma, so cyclophosphamide was hypothesized to eliminate this barrier and enable transferred immune T cells to regress tumors. Cyclophosphamide at 100 mg/kg eradicated splenic suppressor T cells in tumor‑bearing donors while sparing immune T cells. The combination of cyclophosphamide and tumor‑immune spleen cells induced complete, permanent regression of small and large Meth A tumors, an effect abrogated by splenic T cells from tumor donors and attributable to the removal of cyclophosphamide‑sensitive suppressor T cells.

Abstract

On the basis of preceding studies showing that tumor-induced, T cell-mediated immunosuppression serves as an obstacle to adoptive immunotherapy of the Meth A fibrosarcoma, it was predicted that cyclophosphamide treatment of tumor bearers would remove this obstacle and allow passively transferred immune T cells to cause tumor regression. It was found that infusion of immune spleen cells alone had no effect on tumor growth, and cyclophosphamide alone caused a temporary halt in tumor progression. In contrast, combination therapy consisting of intravenous injection of 100 mg/kg of cyclophosphamide followed 1 h later by intravenous infusion of tumor-immune spleen cells caused small, as well as large tumors, to completely and permanently regress. Tumor regression caused by combination therapy was completely inhibited by intravenous infusion of splenic T cells from donors with established tumors, but not by spleen cells from normal donors. These suppressor T cells were eliminated from the spleen by treating the tumor-bearing donors with 100 mg/kg of cyclophosphamide. Immune T cells, in contrast, were resistant to this dose of cyclophosphamide. These results show that failure of intravenously-infused, tumor-sensitized T cells to cause regression of the Meth A fibrosarcoma growing in its syngeneic or semi-syngeneic host is caused by the presence of a tumor-induced population of cyclophosphamide-sensitive suppressor T cells.