IMMUNIZATION WITH MUTAGEN-TREATED (TUM-) CELLS CAUSES REJECTION OF NONIMMUNOGENIC RAT GLIOMA ISOGRAFTS

The ethyl-N-nitrosourea-induced rat glioma N32 was treated with the mu tagenic compound N-methyl-N'-nitro-N-nitrosoguanidine and the survivin g cells cloned by limiting dilution. Out of 20 clones tested 8 did not produce tumors subcutaneously even after challenge doses 3 log units above the minimal tumor dose for N32. All of 5 clones grew in a retard ed manner intracerebrally but produced tumors in some animals. Preimmu nizations with three of the rejected clones (tum-) gave protection aga inst subcutaneous and intracerebral isografts of the unmutated N32. Th is effect could be enhanced if the cells used for immunizations were p retreated with interferon gamma (IFNgamma) for 48 h. If immunizations were started subsequent to challenge, only immunization with one of tw o tested tum- clones pretreated with IFNgamma induced significant reje ction against intracerebral N32 isografts. Both N32 and its tum- clone s were MHC class I positive and MHC class II negative. IFNgamma treatm ent enhanced the MHC class I expression with 20%-90% on the tum- clone s and with 40% on N32. MHC class II expression could be induced on N32 cells after 7 days of IFNgamma treatment but not on any of the tum- c lones tested. We conclude that the enhancing effect of IFNgamma treatm ent on tumor isograft rejection may depend on up-regulation of MHC cla ss I but not of MHC class II. This investigation demonstrates that it is possible to induce rejection of weakly immunogenic intracerebral br ain tumors by immunization with selected highly immunogenic tumor cell mutants. In conjunction with relevant cytokines, the cross-protective effect of these tum- variants might be further enhanced and serve as a model for immunotherapy against malignant human brain tumors.