Abstract
The present study investigates some of mechanisms for tumor-specific Lyt-1+2− T cell-mediated tumor cell eradication in vivo through analyses of tumor specificity in the afferent tumor recognition and efferent rejection phases. When C3H/He mice which had acquired immunity against syngeneic MH134 hepatoma were challenged with other syngeneic X5563 plasmacytoma cells, these mice failed to exhibit any inhibitory effect on the growth of X5563 tumor cells. However, the inoculation of X5563 tumor cells into the MH134-immune C3H/He mice together with the MH134 tumor cells resulted in appreciable growth inhibition of antigenically distinct (bystander) X5563 tumor cells. Although the growth of X5563 cells was inhibited in an antigen-nonspecific way in mice immunized to antigenically unrelated tumor cells (bystander effect), the activation of Lyt-1+2− T cells leading to this effect was strictly antigen-specific. Such a bystander growth inhibition also required the admixed inoculation of the bystander (X5563) and specific target (MH134) tumor cells into a single site in mice immunized against the relevant MH134 tumor cells. Furthermore, the results demonstrated that Lyt-1+2− T cells specific to MH134 tumor cells were responsible for mediating the growth inhibition of antigenically irrelevant (bystander) and relevant tumor cells. These results are discussed in the context of cellular and molecular mechanisms involved in the Lyt-1+2− T cell-initiated bystander phenomenon.
Keywords: Tumor Cell, Growth Inhibition, Tumor Specificity, Bystander Effect, Plasmacytoma
Footnotes
This work was supported by Special Project Research-Cancer Bioscience from the Ministry of Education, Science and Culture
References
- 1.Bast RC, Jr, Zbar B, Rapp HJ. Local antitumor activity of a primary and an anamnestic response to a syngeneic guinea pig hepatoma. J Natl Cancer Inst. 1975;55:989. doi: 10.1093/jnci/55.4.989. [DOI] [PubMed] [Google Scholar]
- 2.Billingham RE, Streilein JW, Zakarian S. Specificity of the homograft reaction. In: Forscher BK, Houck JC, editors. Immunopathology of inflammation. Amsterdam: Excerpta Medica; 1971. [Google Scholar]
- 3.Cerottini JC, Brunner KT. Cell-mediated cytotoxicity, allograft rejection and tumor immunity. Adv Immunol. 1974;18:67. doi: 10.1016/s0065-2776(08)60308-9. [DOI] [PubMed] [Google Scholar]
- 4.Fujiwara H, Hamaoka T, Teshima K, Aoki H, Kitagawa M. Preferential generation of killer or helper T-lymphocyte activity directed to the tumor-associated transplantation antigens. Immunology. 1976;31:239. [PMC free article] [PubMed] [Google Scholar]
- 5.Fujiwara H, Fukuzawa M, Yoshioka T, Nakajima H, Hamaoka T. The role of tumor-specific Lyt-1+2− T cells in eradicating tumor cells in vivo. I. Lyt-1+2− T cells do not necessarily require recruitment of host's cytotoxic T cell precursors for implementation of in vivo immunity. J Immunol. 1984;133:1671. [PubMed] [Google Scholar]
- 6.Fujiwara H, Takai Y, Sakamoto K, Hamaoka T. The mechanism of tumor growth inhibition by tumor-specific Lyt-1+2− T cells. I. Antitumor effect of Lyt-1+2− T cells depends on the existence of adherent cells. J Immunol. 1985;135:2187. [PubMed] [Google Scholar]
- 7.Fukuzawa M, Fujiwara H, Yoshioka T, Itoh K, Hamaoka T. Tumor-specific Lyt-1+2− T cells an reject tumor cells in vivo without inducing cytotoxic T lymphocyte responses. Transplant Proc. 1985;17:599. [Google Scholar]
- 8.Galli SJ, Bast RC, Bast BS, Jr, Isomura T, Zbar B, Rapp HJ, Dvorak HF. Bystander suppression of tumor growth: Evidence that specific targets and bystanders are damaged by injury to a common micorvasculature. J Immunol. 1982;129:890. [PubMed] [Google Scholar]
- 9.Greenberg PD, Cheever MA, Fefer A. Eradication of disseminated murine leukemia by chemoimmunotherapy with cyclophosphamide and adoptively transferred immune syngeneic Lyt-1+2− lymphocytes. J Exp Med. 1981;154:952. doi: 10.1084/jem.154.3.952. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Greenberg PD, Kern DE, Cheever MA. Therapie of disseminated murine leukemia with cyclophosphamide and immune Lyt-1+2− T cells. Tumor eradication does not require participation of cytotoxic T cells. J Exp Med. 1985;161:1122. doi: 10.1084/jem.161.5.1122. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Herberman RB. Cell-mediated immunity to tumor cells. Adv Cancer Res. 1974;19:207. doi: 10.1016/s0065-230x(08)60055-x. [DOI] [PubMed] [Google Scholar]
- 12.Jessup JM, Madden RE. Further evidence of a nonspecific rejection in hosts immunized with non-cross-reacting tumors. Proc Am Assoc Cancer Res. 1971;12:55. [Google Scholar]
- 13.Klein G, Klein E. Genetic studies of the relationship of tumour host cells: detection of an allelic difference at a single gene locus in a small fraction of a large tumour-cell population. Nature. 1956;178:1389. doi: 10.1038/1781389a0. [DOI] [PubMed] [Google Scholar]
- 14.Klein E, Klein G. Specificity of homograft rejection in vivo, assessed by inoculation of artificially mixed compatible and incompatible tumor cells. Immunology. 1972;5:201. [PubMed] [Google Scholar]
- 15.Mintz B, Silvers WK. Histocompatibility antigens on melanoblasts and hair follicle cells: cell-localized homograft rejection in allophenic skin grafts. Transplantation. 1970;9:497. doi: 10.1097/00007890-197005000-00009. [DOI] [PubMed] [Google Scholar]
- 16.Nakajima H, Fujiwara H, Takai Y, Izumi Y, Sano S, Tsuchida T, Hamaoka T. Studies on macrophage-activating factor (MAF) in anti-tumor immune responses. I. Tumor-specific Lyt-1+2− T cells are required for producing MAF able to generate cytolytic as well as cytostatic macrophages. J Immunol. 1985;135:2199. [PubMed] [Google Scholar]
- 17.Ringertz N, Klein E, Revesz L. Growth of small compatible tumor implants in presence of admixed radiation-killed or incompatible tumor cells. Cancer. 1959;12:697. doi: 10.1002/1097-0142(195907/08)12:4<697::aid-cncr2820120412>3.0.co;2-3. [DOI] [PubMed] [Google Scholar]
- 18.Sakamoto K, Fujiwara H, Nakajima H, Yoshioka T, Takai Y, Hamaoka T. The mechanism of tumor growth inhibition of tumor-specific Lyt-1+2− T cells. II. Dual requirements of adherent cells for activating Lyt-1+2− T cells as well as for functioning as tumoricidal effectors activated by factor(s) from Lyt-1+2− T cell. Gann (in press) [PubMed]
- 19.Weissman IL. Tumor immunity in vivo: evidence that immune destruction of tumor leaves “bystander” cells intact. J Natl Cancer Inst. 1973;51:443. [PubMed] [Google Scholar]
- 20.Yoshioka T, Sato S, Fujiwara H, Hamaoka T. The role of anti-asialo GMI anbibody-sensitive cells in the implementation of tumor-specific T cell-mediated immunity in vivo. Gann. 1986;77:825. [PubMed] [Google Scholar]
- 21.Zbar G, Wepsic HT, Borsos T, Rapp HJ. Tumor-graft rejection in syngeneic guinea pigs: evidence for a two-step mechanism. J Natl Cancer Inst. 1970;44:473. [PubMed] [Google Scholar]
