Summary
We report the development of cytotoxic T lymphocytes specific for an allogeneic brain tumor in a rat model. DA strain cytotoxic T cell precursors stimulated by an allogeneic tumor (9L gliosarcoma) from the Fischer rat could generate a population of cytotoxic T lymphocytes that lysed the allogeneic 9L tumor but failed to lyse other targets, including Fischer concanavalin-A(ConA)-stimulated lymphoid blast targets. DA T cells depleted of reactivity to the Fischer haplotype (DA-f) retained reactivity to the 9L tumor, demonstrating that T cell precursors with specificity for normal Fischer alloantigens were not required for the generation of a response to the 9L Fischer tumor. The preferential lysis of the tumor target did not simply reflect a higher density of Fischer target antigens on the tumor than that found on normal Fischer ConA blast targets. First, the relative densities of class I antigen on the 9L tumor and normal Fischer ConA blasts were comparable. Second, cytotoxic T cells could not be generated from DA-f precursors when Fischer ConA blasts were used as stimulators. If DA-f T cells were simply responding to the higher density of Fischer antigen found on 9L tumor, it would have been expected that the ConA blasts expressing comparable levels of antigen to that found on the tumor would have generated cytotoxicity for both the 9L and ConA targets. We conclude that the cytotoxic T cells are specific for a determinant expressed only by the tumor. Such tumor-specific cytotoxic T cells could be useful in vivo for adoptive immunotherapy of brain tumors.
Similar content being viewed by others
References
Albright AL, Gill TJ, Geyer SJ (1977) Immunogenetic control of brain tumor growth in rats. Cancer Res 27: 2512
Bellgrau D (1983) Induction of cytotoxic T cell precursors in vivo. Role of T helper cells. J Exp Med 157: 1505
Bellgrau D, Lagarde A-C (1985) In vivo separation of two classes of T cells as determined by negative selection after the injection of uv-treated allogeneic lymphoid cells. Proc Natl Acad Sci USA 82: 5136
Bellgrau D, Lagarde A-C (1990) Cytotoxic T cell precursors with low level CD8 in the diabetes-prone Biobreeding rat: implications for generation of an autoimmune T-cell repertoire. Proc Natl Acad Sci USA 87: 313
Bellgrau D, Talmage DW (1986) T cells can be cytotoxic without making Interleukin 1: a model of separate pathways of induction. Proc Natl Acad Sci USA 83: 3412
Bellgrau D, Zoller M (1983) Cytotoxic T lymphocyte responses to spontaneous tumors: immunogenicity dependent on the recognition of processed tumor antigens. J Immunol 130: 2005
Bennick JR, Doherty PC (1978) Different rules govern help for cytotoxic T cells and B cells. Nature 276: 829
Bhondeley MK, Mehra RD, Mehra NK, Mohapatra AK, Tandon PN, Roy S, Bijlani V (1988) Imbalances in T cell subpopulations in human gliomas. J Neurosurg 68: 589
Chiu KM, Harris JE, Droin JS, Slayton W, Braun DP (1983) The immunological response of Wistar rats to the intracranially implanted C-6 glioma cell line. J Neurooncol 1: 365
Dorsch S, Roser B (1975) T cells mediate transplantation tolerance. Nature 258: 233
Fischer-Lindahl K, Wilson DB (1977) Histocompatibility antigen-activated cytotoxic T lymphocytes II. Estimates of the frequency and specificity of precursors. J Exp Med 145: 508
Fontana A, Hengartner H, deTribolet N, Weber E (1984) Glioblastoma cells release Interleukin 1 and factors inhibiting interleukin-2-mediated effects. J Immunol 132: 1837
Fuchs HE, Bullard DE (1988) Immunology of transplantation in the central nervous system. Appl Neurophysiol 51: 278
Gately MK, Glaser M, Dick SJ, Mettetal RW, Kornblith PL (1982) In vitro studies on the cell-mediated immune response to human brain tumor I. Requirement for third party stimulator lymphocytes in the induction of cell-mediated cytotoxic responses to allogeneic cultured gliomas. JNCI 69: 1245
Geyer SJ, Landry A (1983) Immunogenetic and immunologic aspects of gliosarcoma growth in rats. Lab Invest 49: 436
Gowans JL (1962) The fate of parental strain small lymphocytes in F1 hybrid rats. Ann NY Acad Sci 99: 432
Grimm EA, Mazumder A, Zhang HZ, Rosenberg SA (1982) Lymphokine-activated killer cell phenomenon. Lysis of natural killer-resistant fresh solid tumor cells by interleukin 2-activated autologous human peripheral blood lymphocytes. J Exp Med 155: 1823
Heath WR, Hurd ME, Carbone FR, Sherman LA (1989) Peptide-dependent recognition of H-2Kb by alloreactive cytotoxic T lymphocytes. Nature 341: 749
Ingram M, Buckwalter JG, Jacques DB, Freshwater DB, Abts RM, Techy GB, Migagi K, Shelden CH, Rand RW, English LW (1990) Immunotherapy for recurrent malignant glioma: an interim report on survival. Neurol Res 12: 265
Jacobs SK, Wilson DJ, Melin G, Parham CW, Holcomb B, Kornblith PL, Grimm EA (1986) Interleukin-2 and lymphokine activated killer (LAK) cells in the treatment of malignant glioma: clinical and experimental studies. Neurol Res 8: 81
Kruse CA, Mitchell DH, Lillehei DO, Johnson SD, McCleary L, Moore GE, Waldrop S, Mierau GW (1989) Interleukin-2-activated lymphocytes from brain tumor patients. A comparison of two preparations generated in vitro. Cancer 64: 1629
Kruse CA, Lillehei KO, Mitchell DH, Kleinschmidt-Demasters B, Bellgrau D (1990) Analysis of Interleukin-2 and various effector cell populations in adoptive immunotherapy of 9L gliosarcoma: allogeneic cytotoxic T lymphocytes prevent tumor take. Proc Natl Acad Sci USA 87: 9577
Lafreniere R, Rosenberg SA (1985) Adoptive immunotherapy of murine hepatic metastases with lymphokine activated killer (LAK) cells and recombinant interleukin 2 (rIL2) can mediate the regression of both immunogenic and nonimmunogenic sarcomas and an adenosarcoma. J Immunol 135: 4273
Lillehei KO, Kruse CA, Mitchell DH, Johnson SD, McCleary EL (1989) Adoptive immunotherapy of recurrent glioma using interleukin-2-stimulated lymphocytes. Surg Forum 40: 493
Lillehei KO, Mitchell DH, Johnson SD, McCleary EL, Kruse CA (1991) Long-term follow-up of patients with recurrent gliomas treated with adjuvant adoptive immunotherapy. Neurosurgery 28: 16
Marrack P, Kappler J (1990) T cells can distinguish between allogeneic major histocompatibility complex products on different cell types. Nature 332: 840
Medewar PB (1948) Immunity to homologous grafted skin: III. The fate of skin homografts transplanted to the brain, to subcutaneous tissues, and to the anterior chamber of the eye. Br J Exp Pathol 29: 58
Merchant RE, Grant AJ, Merchant LH, Young HF (1988) Adoptive immunotherapy for recurrent glioblastoma multiforme using lymphokine activated killer cells and recombinant interleukin-2. Cancer 62: 666–671
Merchant RE, Ellison MD, Young HF (1990) Immunotherapy for malignant glioma using human recombinant interleukin 2 and activated autologous lymphocytes. J Neurooncol 8: 173
Molina IJ, Huber BT (1990) The expression of a tissue-specific self peptide is required for allorecognition. J Immunol 144: 2082
Rosenberg SA, Lotze MT, Muul LM, Chang AE, Avis FP, Leitman S, Linehan WM, Robertson CN, Lee RE, Rubin JT, Seipp CA, Simpson CG, White DE (1987) A progress report on the treatment of 157 patients with advanced cancer using lymphokine-activated killer cells and Interleukin-2 or high-dose Interleukin-2 alone. N Engl J Med 316: 889
Salcman M (1990) Epidemiology and factors for survival. In: Apuzzo UJL (ed) Malignant cerebral glioma. American Association of Neurosurgery, Park Ridge, p 95
Wilson DB, Marshak A, Howard JC (1976) Specific positive and negative selection of rat lymphocytes reactive to strong histocompatibility antigens: activation with alloantigens in vitro and in vivo. J Immunol 115: 1030
Wilson DB, Fischer-Lindahl K, Wilson D, Sprent J (1977) The generation of killer cells to TNP modified allogeneic targets by lymphocyte populations negatively selected to strong alloantigens. J Exp Med 146: 361
Zoller M, Bellgrau D, Axberg I, Wigzell H (1982) Natural killer cells do not belong to the recirculating lymphocyte pool. Scand J Immunol 15: 159
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Redd, J.M., Lagarde, AC., Kruse, C.A. et al. Allogeneic tumor-specific cytotoxic T lymphocytes. Cancer Immunol Immunother 34, 349–354 (1992). https://doi.org/10.1007/BF01741557
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF01741557