H-2K double transfectants of tumor cells as antimetastatic cellular vaccines in heterozygous recipients: Implications for the T cell repertoire

In this study we demonstrate that antitumor CTL repertoire restricted to a single MHC class I allele is higher in homozygous than in heterozygous mice. Consequently, transfection of two parental H-2K genes, but not of a single H-2K gene into a highly metastatic H-2K-negative tumor clone, resulted in abrogation of metastatic properties in F₁ recipients. Clones of the 3LL carcinoma, which are low H-2K^b expressors, are nonimmunogenic and highly metastatic. Transfection of H-2K genes converted cells of such clones to nonmetastatic in syngeneic homozygous mice. However, in semi-syngeneic heterozygous mice, single H-2K transfectants retained their metastatic phenotype. In such heterozygous mice, i.e., in (H-2^d × H-2^b)F₁, or in (H-2^k × H-2^b)F₁, transfection of the two parental H-2K genes was required for complete abolishment of the metastatic phenotypes. In fact, in these heterozygous animals, even the local growth (i.e., tumorigenicity) of the double H-2K transfectants was significantly suppressed. These observations are attributed to the difference between homozygous and heterozygous mice with regard to the T cell repertoire restricted to a single H-2K-tumor-associated antigen complex. The reduced tumorigenicity and the complete abrogation of the metastatic phenotype was a function of a high immunogenic competence of the double transfectants in F₁ heterozygous mice, which was significantly higher than that of single transfectants, as measured by the induction of CTL and of their precursors. Immunization of F₁ mice by inactivated double transfectants conferred protection against metastasis formation by a subsequent graft of the parental D122 cells. Single transfectants were only marginally effective in conferring such protection. Applying an immunotherapy protocol, we observed that a series of vaccinations with double transfectants of animals already carrying a parental tumor reduced significantly the generation of metastasis by the otherwise highly metastatic D122 cells.