Variable response to a candidate cancer vaccine antigen: MHC control of the antibody response in the rat to avian erythroblastosis virus (AEV)-encoded epithelial growth factor receptor but not AEV-encoded thyroid hormones receptor

A problem likely to be encountered in any cancer immunotherapy based on vaccination with a single protein or peptide is variation in the host response. A particularly informative example is provided by the two oncogenic proteins, one intracellular and the other extracellular, encoded by the avian erythroblastosis virus (AEV), homologs of the thyroid hormones receptor (THsR) and the epithelial growth factor receptor (EGFR), respectively. Antibodies to these two proteins were assayed by radioimmune precipitation (RIP) in sera from MHC-congenic rats immunized by virally induced tumors. Among the four haplotypes tested, RT1(1) rats exhibited a significantly lower response to the EGFR homolog than the high responders RT1c and RT1u, while RT1a rat strains had an intermediate response. Analysis of the recombinant haplotype RT1ac indicated that the response is controlled, as expected, by the class II locus of the MHC. In contrast, these rat strains responded uniformly to the intracellular THsR homolog. These results support the hypothesis that MHC restriction of the response to self-related proteins reflects mainly a tolerance mechanism. They sound a note of warning for cancer vaccine development, and also one of positive advice. The likelihood of MHC restriction suggests that a widely applicable polyvalent vaccine should be the final aim in cancer immunotherapy. Yet, paradoxically, evidence of MHC restriction can help establish that a candidate vaccine is likely to prove effective.