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Expression of a Transfected H-2K^b Gene in B16 Cells Correlates with Suppression of Liver Metastases in Triple Immunodeficient Mice¹

Department of Radiation Oncology, Division of Radiation and Cancer Biology, New England Medical Center, Boston, Massachusetts 02111 [L. C., S. G-C.]; Department of Biology and Genetics, University of Milan Milan, Italy [A. M.]; and Departments of Pathology [H. R. B.], Surgery [G. L. W.], Radiation Medicine [K. W. L.], and the Cancer Center [K. J. I.], Massachusetts General Hospital, Boston, Massachusetts 02114

In vivo experiments performed with NIH (nu/nu, bg/bg, xid/xid) triple immunodeficient (TD) mice revealed the striking ability of i.v. injected B16-F1 and B16-F10 murine melanoma cells to colonize not only the lungs but also the liver of TD mice. Subsequently, B16 melanoma cell cultures, which express very low levels of H-2K^b antigen, were cotransfected with plasmids pRSVneo, containing the neomycin resistance gene, and 6-2B1pMT, expressing the H-2K^b complentary DNA under the control of the metallothionein enhancer-promoter. Several neomycin-resistant clones were analyzed for H-2K^b and H-2D^b expression by RNase protection and flow cytometry assays. All parental lines and transfected clones expressed normal levels of H-2D^b mRNA, while only some of the transfected clones expressed easily detectable levels of H-2K^b mRNA. Moreover, in these clones H-2K^b expression could be enhanced in the presence of Zn²⁺, indicating that the metallothionein enhancer was functioning properly. Parental cells and transfected clones were injected i.v. in TD mice to assess the possible involvement of H-2K^b antigen in regulating the metastatic potential of B16 melanoma cells. We observed a remarkable correlation between expression of H-2K^b antigen and suppression of liver-specific metastases in TD mice. Identical results were obtained when we gave TD mice injections of mixed populations of transfectants expressing H-2K^b antigen, obtained by fluorescence-activated cell sorting. These experiments allowed us to rule out the possibility that the observed changes in metastatic potential were due to clonal variability among individual transfected clones. Taken together, the results of our in vivo studies with immunodeficient mice support the notion that specific major histocompatibility complex Class I molecules modulate the metastatic potential of malignant cells also by mechanisms which are independent of their well-established role in antigen presentation.

¹ This work was supported in part by grants from the NIH. L. C. is a Fellow sponsored by the Italian Association for Cancer Research (AIRC).

² To whom requests for reprints should be addressed, at Department of Radiation Oncology, New England Medical Center, Box 824, 750 Washington Street, Boston, MA 02111.

Received 2/21/92. Accepted 5/ 7/92.