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Immunosuppression in murine renal cell carcinoma. I. Characterization of extent, severity and sources
1Department of Chemistry, Cleveland State University, Ohio 44115.
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.
Insights
Renal cell carcinoma (Renca) in mice impairs multiple immune responses, including lymphokine-activated killer (LAK) cells and natural killer activity. This immune suppression is caused by suppressor cells and Renca cells themselves.
Area of Science:
- Immunology
- Oncology
- Cellular Biology
Background:
- Tumor-induced immunosuppression is a significant barrier to effective cancer treatment.
- Understanding the mechanisms of immune evasion by renal cell carcinoma (Renca) is crucial for developing novel therapies.
Purpose of the Study:
- To investigate the impact of Renca on various cell-mediated immunological responses in mice.
- To identify the sources and mechanisms of tumor-induced immune suppression.
Main Methods:
- Assessing lymphokine-activated killer (LAK) cell activity, natural killer (NK) cell activity, cytotoxic T lymphocyte (CTL) development, and delayed hypersensitivity (DTH) responses in Renca-bearing mice.
- Kinetic analysis of immune response impairment using LAK assays.
- Investigating the role of suppressor cells and Renca cells in immune suppression through in vitro and adoptive transfer experiments.
Main Results:
- Renca-bearing mice exhibited significantly reduced LAK cell activity, NK cell activity, CTL development, and DTH responses compared to normal mice.
- Immune suppression was evident as early as 1 week after tumor inoculation and peaked by 3 weeks.
- Suppressor cells found in the spleen, but not bone marrow, of tumor-bearing mice were responsible for inhibiting LAK cell generation and adoptive transfer studies confirmed their role in suppressing NK activity and DTH responses.
- Irradiated Renca cells directly suppressed the proliferation of splenic cells and inhibited LAK cell development in vitro.
Conclusions:
- Renca induces a profound and multi-faceted immunosuppression in mice, affecting multiple arms of the cell-mediated immune system.
- Both suppressor cells and the tumor cells themselves contribute to this immune evasion.
- The findings highlight the complexity of tumor-induced immune suppression and provide a basis for further research into therapeutic strategies targeting these mechanisms.