The inability of adoptive immunotherapy to eradicate tumor cells in radiation-induced chimeric mice: the possible down-regulation of intratumor immune amplification.

Abstract

Tumors were eradicated following adoptive immunotherapy of (C57BL/6J X DBA/2J) F1 (B6D2F1) hybrid mice bearing the C57B1/6J (B6) sarcoma, MCA/76-9, by treatment with cyclophosphamide (CY) and adoptively transferred tumor-sensitized B6D2F1 T cells. Identical treatment of B6----B6D2F1 or DBA----B6D2F1 chimeric tumor-bearing mice resulted in temporary tumor regression only. Immunotherapy in both systems resulted in the appearance at the tumor site of large numbers of T lymphocytes and macrophages, which were shown to be derived from the adoptively transferred donor immune B6D2F1 cells or from the original reconstituting bone marrow respectively. The TAC and TAL isolated from either B6D2F1 or chimeric mice expressed potent toxicity in vitro towards tumor target cells. In addition, TAC from both systems inhibited tumor growth in a Winn assay in an immunologically specific manner. Suppressor cells detected in spleens 8 days after CY injection of normal B6, DBA, B6D2F1 hybrid and chimeric mice and also after adoptive immunotherapy of tumor-bearing B6, B6D2F1 and chimeric mice and were shown to persist in the spleens of chimeric mice for at least 31 days after adoptive immunotherapy. In contrast, spleen cells taken 31 days after therapy of B6D2F1 mice did not contain detectable suppressor cells and were able to induce tumor eradication when adoptively transferred to CY-treated tumor-bearing B6D2F1 mice. The possibility is discussed that two forms of suppressor mechanisms are induced after adoptive immunotherapy of chimeric mice and that they may down-regulate donor T cell responses at the tumor site.