Immunosuppression in murine renal cell carcinoma. I. Characterization of extent, severity and sources

Abstract

Four cell-mediated immunological responses related to tumor elimination have been examined in mice injected with a transplantable renal cell carcinoma (Renca). Lymphokine-activated killer (LAK) cells generated in vitro from spleen cells of normal mice were capable of attacking Renca, EL-4, P815 and YAC-1 targets, but those from mice bearing Renca for 3 weeks could not. Natural killer activity, stimulated in vivo by administering poly(I) poly(C), was less than 50% of normal in Renca-bearing hosts. In addition, development of cytotoxic T lymphocytes to allogeneic targets was markedly inhibited in mice possessing the renal tumor. Finally, the delayed hypersensitivity response to a dermally applied hapten was approximately 70% less than normal in tumor-bearing mice, no matter whether the tumor existed subcutaneously or intrarenally. A kinetic study of the development of non-responsiveness using the LAK assay showed onset of poor response at 1 week, which became maximal within 3 weeks following receipt of tumor subcutaneously. The immunological depression was seen to be attributable in part to suppressor cells present among spleen cells but not bone marrow cells of tumor-bearing hosts. The suppressor cells prevented in vitro LAK generation by normal spleen cells and, when adoptively transferred to normal mice, they inhibited natural killer stimulation and delayed hypersensitivity generation. Another source of immunological down-regulation was provided by Renca cells themselves. Incorporation of Renca cells that had been X-irradiated with 30,000 rad into cultures of normal and Renca-derived splenic cells suppressed replication of both almost completely. Furthermore, the presence of X-irradiated Renca cells in cultures of normal spleen cells prevented development of LAK cells. Thus, the suppression seen in Renca-bearing mice derives from multiple sources and whether each is in any way related to the other has been discussed. Identification of the phenotypes of cells responsible for the lymphoid cell-mediated suppression and examination of its elimination are communicated in the companion paper.