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Immunological Characteristics of Immunogenic Variants Induced in the MCA-F Murine Fibrosarcoma Using 1-Methyl-3-nitro-1-nitrosoguanidine, 5-Aza-2'-deoxycytidine, or Ultraviolet Radiation¹

Departments of Immunology [W. S., S. J. L.] and Cell Biology [P. F.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

The purpose of this study was to compare the frequency of generation and in vivo cross-reactivity of highly immunogenic (Imm⁺) clones induced in a single parental murine fibrosarcoma cell line MCA-F by 4 weekly treatments with either UV-B radiation, 1-methyl-3-nitro-1-nitrosoguanidine, or 5-aza-2'-deoxycytidine. These agents are believed to induce Imm⁺ variants by different mechanisms. The frequency of Imm⁺ variant generation was similar for the three different protocols, suggesting that the frequency of Imm⁺ generation was related more closely to the cell line than the inducing agent used. The strength of the immunogenic phenotype, however, was better correlated to the agent used, since 1-methyl-3-nitro-1-nitrosoguanidine yielded clones with the strongest immunogenicities. Three of four UV-B-induced Imm⁺ clones grew preferentially in chronically UV-irradiated syngeneic mice, a phenotype associated with UV-induced skin tumors. Cross-reactivity was tested with two Imm⁺ clones from each treatment group in a modified immunoprotection assay that selectively engendered antivariant, but not antiparental, immunity. Under these conditions each clone, except one, protected against itself. The clones displayed a complex pattern of cross-protection. Intervariant cross-protection was sensitive to the challenge dose, suggesting possible differences in the strengths of the cross-reacting immunities. Conversely, parental cross-protection was observed only with high immunizing multiplicities of Imm⁺ cells. The clones expressed the Imm⁺ phenotype in both C3H/HeN and C3H/HeJ mice, suggesting that expression of mammary tumor virus antigens did not account for the strong antitumor immune response. We also investigated whether the level of major histocompatibility complex class 1 or class 2 expression and immunogenic phenotype were correlated. Flow cytofluorography using haplotype-specific anti-K^k and anti-D^k monoclonal antibodies did not reveal a consistent difference in the constitutive or -interferon-induced class 1 expression by Imm⁺ clones. However, we did observe a significant increase in the constitutive expression of IA^k by most of the Imm⁺ variant clones. Together, these data demonstrate that in this system Imm⁺ variants engendered by a variety of meoantigens, independent of parental tumor antigens or major histocompatibility complex antigen expression.

¹ Supported by a Biomedical Research Support Grant RR5511-23 (S. J. L.), and by Grants CA39855 and CA41225 (P. F.) from the National Cancer Institute.

² Recipient of an R. E. "Bob" Smith Predoctoral Fellowship in Immunology.

³ To whom requests for reprints should be addressed, at Department of Immunology, Box 178, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030.

Received 9/ 8/88. Revised 1/27/89. Revised 5/ 2/89. Accepted 5/ 4/89.