The specificity of concomitant tumor immunity at large tumor volumes

Abstract

Two antigenically distinct fibrosarcomas, designated BP-8 and BP-9, induced in syngeneic C3H/HeN mice by 3,4-benzo(a)pyrene were used to study tumor-specific immunity, concomitant tumor immunity and the effect of large tumor volumes on the loss of immunological reactivity. Two groups of mice were immunized to the BP-8 tumor by amputation of growing BP-8 isografts. One group was rechallenged with the BP-8 cells, and tumor growth was not noted. Both groups of mice then received an inoculum of BP-9 cells that grew to palpable tumors to the same extent as in control mice. BP-8-immunized mice bearing progressively larger PB-9 tumors were sacrified at varying intervals after the BP-9 isograft. Tumor weight was recorded as a percentage of total body weight and viable spleen cells from these animals were tested in vitro for cytotoxicity against BP-8 and BP-9 cells in the [125I]iododeoxyuridine microcytotoxicity assay. Spleen cells from untreated mice were used as controls. The mice with growing BP-9 tumors developed an immune reaction against the tumor antigens which increased with time from initial tumor isograft and with increasing tumor size up to a definite but variable limit. Cytotoxicity to BP-9 cells rose from 18% when the BP-9 tumor was not palpable to a maximum of 77% when the tumor represented 5 to 10% of the total body weight. Cytotoxicity to BP-9 fell progressively as tumor size exceeded 15% of the total body weight and approached the 10% background cytotoxicity of control lymphocytes to BP-9 cells, when the tumor weight achieved 25% of the animal's weight. Conversely, cytotoxicity of lymphocytes against the BP-8 tumor did not vary significantly and remained about 41 to 44% over the same interval even while specific reactivity to BP-9 cells significantly decreased. In addition, with time, lymphocyte-mediated cytotoxicity to the BP-8 tumor increased from 41 to 70% if the BP-8-immunized mice had been rechallenged with antigenically identical BP-8 cells prior to the BP-9 isograft. These data suggest that loss of immunoreactivity at large tumor volumes is tumor and, presumably, antigen specific. No evidence of a generalized immune paralysis was demonstrated, since the mice always maintained immunity to the BP-8 tumor despite progressive and lethal growth of the antigenically distinct BP-9 tumor.