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To study the immune response against oncogene-transformed tumors, C3H/HcN mouse embryo fibroblasts (MEF) were transfected with an activated allele of the H-ras proto-oncogene VaII2 and a dominant-negative allele of the murine p53 tumor suppressor gene VaII35. Transformed cell lines were derived and found to be tumorigenic in syngeneic mice. Immunization with irradiated p53 + ras-transformed MEF, but not primary MEF or unrelated syngeneic cells, protected mice from subsequent challenge with live tumor cells. The role of different immune cell subsets in the effector phase of anti-tumor immunity induced by immunization with p53 + ras-transformed MEF was investigated by in vivo antibody depletion experiments. Immunized mice depleted of CD8+ T, NK or B cells were resistant, but depletion of CD4+ T cells rendered mice susceptible to tumorigenic challenge. In contrast to the tumor-specific immune responses mounted against most chemically or UV-induced tumors, a series of independently derived p53 + ras-transformed MEF were cross-reactive in tumor rejection assays. In addition, immunization with C3H-derived L-929 cell lines expressing single gene products H-ras or p53 did not protect mice against tumorigenic challenge with p53 + ras-transformed tumors. However, MEF transformed by expression of either H-ras or p53 were cross-protective in vivo. Our data suggest that the p53 + ras-transformed MEF share tumor rejection antigens which are also induced by single gene transformation of the parental primary cell but are not the products of oncogenic ras or p53 protein.

Rat adenocarcinoma 13762 was adapted to continuous growth in culture and used in a variety of experiments to investigate the immune response to inoculation of animals with replication-defective tumor cells. The results demonstrate that 13762 cells express tumor-specific tumor rejection antigens that elicit protective immunity to tumorigenic challenge. By several criteria there is no apparent humoral component of the anti-tumor immunity; however, anti-tumor immunity is characterized by nylon-wool nonadherent spleen T cells. Anti-tumor T cells demonstrate tumoricidal activity in local adoptive transfer assays and are not found in spleens of naive animals or animals immunized against either nontumorigenic Rat 1 cells or a syngeneic fibrosarcoma. Despite the expression of tumor rejection antigens 13762 tumor, and the demonstrable ability of injection of irradiated tumor to induce anti-tumor immunity, tumors elicited in unimmunized syngeneic animals grow progressively. The reasons for growth of antigenic tumor are unknown but are shown not to be due to defective antigen expression in 13762 tumor since, in addition to being able to elicit T cell immune response in immunized animals, 13762 tumor expresses MHC Class I molecules and can be a target for allogeneic T cell recognition in vitro. These data suggest that in tumor-bearing animals an effective anti-tumor immune response is either not initiated or down-regulated. Since animals bearing 13762 tumors can be immunized against an unrelated syngeneic sarcoma, can produce humoral responses to several protein antigens, and can produce delayed type hypersensitivity response against dinitrofluorobenzene, the immune response to 13762-induced tumors appears specifically suppressed. In support of this contention, 13762 cells express high levels of transforming growth factor beta 1 in vitro which is postulated to impact upon the nascent anti-tumor immune response.