It is possible to cause the regression of a 4-day established tumor in a gamma-irradiated recipient by infusing the recipient with one organ equivalent of splenic T cells from a donor bearing a 9-day, progressive lethal tumor. This finding provides a powerful adoptive immunization assay to follow the generation of concomitant antitumor immunity to progressive tumor growth. Experiments with the SA1 sarcoma, Meth A fibrosarcoma, P815 mastocytoma, P388 lymphoma, and L5178Y lymphoma revealed that progressive tumor growth evoked the generation of tumor-sensitized T cells that, on passive transfer, could cause the regression of an established tumor in a gamma-irradiated (500 rad) recipient. These T cells were first detected on day 6 of tumor growth, reached peak numbers on days 9 to 10, and were then progressively lost as the tumor increased in size. Only splenic T cells harvested on days 9 to 10 had the capacity to cause complete and permanent regression of the recipient's tumor. The generation and loss of T cells capable of adoptively immunizing against an established tumor corresponded temporally to the acquisition and loss of concomitant immunity to growth of a tumor cell implant. It was next shown, with the Meth A fibrosarcoma and P815 mastocytoma, that the progressive loss after day 9 of T cells capable of adoptively immunizing against an established tumor was associated with the progressive acquisition of splenic suppressor T cells capable of inhibiting the capacity of tumor-sensitized T cells from preimmunized donors to cause the regression of an established tumor in T cell-deficient (TXB) recipients. These findings are consistent with the hypothesis that there is progressive growth of a concomitant immune response that is actively down-regulated by suppressor T cells before it reaches sufficient magnitude to destroy the tumor. The adoptive immunization assay showed that the T cells that mediate concomitant immunity are Ly1?-?2?+? T cells. In contrast, the cells which suppress the immunity are Ly1?+?2?-?i T cells. Additional experiments have revealed that suppressor T cells function in the adoptive immunization assay by inhibiting the ability of passively transferred helper or memory T cells to give rise to an adoptive cytolytic T-cell response in the tumor-bearing recipient. A knowledge of the kinetics of the generation and T cell-mediated suppression of the concomitant anti-tumor immune response is crucial for the design of successful immunotherapeutic modalities. The experimental results indicate that any attempt to treat a tumor by active or passive immunotherapy represents an attempt to superimpose an immune response on an ongoing concomitant immune response that may be undergoing negative regulation. (TA)

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National Cancer Institute (NCI)
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Experimental Immunology Study Section (EI)
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Trudeau Institute, Inc.
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Rakhmilevich, A L (1994) Failure of anti-T cell monoclonal antibodies to prevent acute tumor allograft rejection is associated with their inability to deplete or inactivate T cells at the site of rejection. Transplantation 58:72-80
Rakhmilevich, A L; North, R J (1994) Elimination of CD4+ T cells in mice bearing an advanced sarcoma augments the antitumor action of interleukin-2. Cancer Immunol Immunother 38:107-12
Rakhmilevich, A L; North, R J; Dye, E S (1993) Evidence inconsistent with a role for tumor necrosis factor in tumor allograft rejection. Transplantation 55:182-6
Rakhmilevich, A L; North, R J; Dye, E S (1993) Presence of CD4+ T suppressor cells in mice rendered unresponsive to tumor antigens by intravenous injection of irradiated tumor cells. Int J Cancer 55:338-43
Dunn, P L; North, R J (1991) Effect of advanced ageing on the ability of mice to cause tumour regression in response to immunotherapy. Immunology 74:355-9
Dunn, P L; North, R J (1991) Effect of advanced aging on ability of mice to cause regression of an immunogenic lymphoma in response to immunotherapy based on depletion of suppressor T cells. Cancer Immunol Immunother 33:421-3
Dunn, P L; North, R J (1991) Selective radiation resistance of immunologically induced T cells as the basis for irradiation-induced T-cell-mediated regression of immunogenic tumor. J Leukoc Biol 49:388-96
North, R J; Dunn, P L; Havell, E A (1991) A role for tumor necrosis factor in poly(I:C)-induced hemorrhagic necrosis and T-cell-dependent regression of a murine sarcoma. J Interferon Res 11:333-40
Rakhmilevich, A L; North, R J (1991) Rapid acquisition of an enhanced capacity to produce tumor necrosis factor, alpha/beta interferon, and interleukin 6 after implantation of tumor cells. Cytokine 3:398-406
North, R J; Awwad, M (1990) Elimination of cycling CD4+ suppressor T cells with an anti-mitotic drug releases non-cycling CD8+ T cells to cause regression of an advanced lymphoma. Immunology 71:90-5

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