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Immunogenic Variants of a Murine Fibrosarcoma Induced by Mutagenesis: Requirement of Viable Cells for Antigen-specific Cross-Protection¹

Departments of Immunology [S. J. L., W. J. S.] and Cell Biology [P. F.], The University of Texas System, M. D. Anderson Hospital and Tumor Institute at Houston, Houston, Texas 77030

The purpose of the study was to investigate the immunological and biological consequences of neoantigen expression by immunogenic tumor variants (Imm⁺) following in vitro treatment with the mutagen 1-methyl-3-nitro-1-nitrosoguanidine. The weakly immunogenic murine fibrosarcoma MCA-F was used because we have previously characterized the tumor-specific transplantation antigen expressed by this tumor. Immunogenic variant clones were obtained at high frequency following four treatments with 1-methyl-3-nitro-1-nitrosoguanidine. The immunogenicity of the Imm⁺ clones was confirmed by their progressive growth in immunosuppressed C3H/HeN mice and their lack of growth in normal syngeneic C3H/HeN mice. The immune response engendered in immunocompetent mice after a single immunization with viable Imm⁺ cells was tumor specific, completely protecting hosts against challenge with 10,000-fold the minimum tumorigenic dose of parental MCA-F cells, but not against 10 minimum tumorigenic doses of the non-cross-reactive tumor MCA-D. The strong cross-protection elicited by Imm⁺ neoantigens against the parental tumor-specific transplantation antigen was not observed when soluble extracts or isolated plasma membranes of Imm⁺ cells were used for immunization. Immunogenic variant cells inactivated using either mitomycin C or -irradiation also demonstrated a significantly diminished immunoprotective activity against challenge with the parent tumor. However, inactivated Imm⁺ cells and their isolated plasma membranes still expressed sufficient neoantigen to completely protect mice against homotypic Imm⁺, but not parental challenge. These results suggest that (a) the MCA-F Imm⁺ variants express neoantigens capable of engendering a strong specific as well as cross-protective immunity against challenge with either the parent or the variant and (b) the associative recognition of neoantigen and TSTA that results in strong cross-protection against challenge with the parent tumor requires immunization with viable Imm⁺ cells for full expression of the immunogenic phenotype.

¹ Supported by USPHS Grants CA38500, CA41525, and CA39853 awarded by the National Cancer Institute, and by the University of Texas Cancer Foundation.

² To whom requests for reprints should be addressed, at Department of Immunology (HMB 178), M. D. Anderson Hospital and Tumor Institute, 6723 Bertner Avenue, Houston, TX 77030.

Received 9/22/86. Revised 11/24/86. Accepted 3/19/87.

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