Abstract
In cocultures of human plancental alkaline phosphatase(PLAP)-positive MO4 tumor cells and human peripheral blood mononuclear cells (PBMC), also containing a heteroconjugate (7E8-OKT3) synthesized between the anti-PLAP monoclonal antibody 7E8 and the anti-CD3 antibody OKT3, and supplemented with low levels of recombinant interleukin-2 (rIL-2), T cells are progressively activated, resulting in tumor cell lysis. To unravel the contribution of PBMC subsets to the generation of this targetable cytotoxicity, PBMC subsets were studied after their isolation by cell sorting, either from fresh PBMC or from PBMC peractivated with OKTe3 and rIL-2. Whereas no targetable cytotoxicity was found in Fc-receptor-bearing CD3-cells, tumor cells were lysed by CD3+ T cells (mostly CD8+) isolated from pre-activated PBMC. When isolated from fresh PBMC, neither the CD8+ T cell subset, nor the total CD3+ T cell population developed significant targetable cytotoxicity, even in the presence of rIL-2. Thus, additional cell types are essential for the CD8+ T cell activation. Indeed. CD4+ T cells isolated from pre-activated but not from fresh PBMC were capable of eliciting cytotoxicity in fresh CD8+ T cells. The non-targeted monocytes were found to be the activators of the CD4+ T cells. In summary, targeting T cells to the surface of a tumor cell is not sufficientper se to achieve activation and lysis. The progressive tumor cell lysis by targeted T cells seems to be initiated by non-targeted monocytes activating CD4+ T cells, these cells in turn promoting CD8+ T cell activation, necessary for the development of cytotoxicity.
Similar content being viewed by others
References
Barr IG, Miescher S, Fliedner V von, Buchegger F, Barras C, Lanzavecchia A, Mach J-P, Carrel S (1989) In vivo localization of a bispecific antibody which targets human T lymphocytes to lyse human colon-cancer cells. Int J Cancer 43:501
Bolhuis RLH, Lamers CHJ, Goey SH, Eggermont AMM, Trimbos JBMZ, Stoter G, Lanzavecchia A, Di Re E, Miotti S, Raspagliesli E, Rivolitini L, Colnaghi MI (1992) Adoptive immunotherapy of ovarian carcinoma with Bs-MAb-targeted lymphocytes: a multicenter study. Int J Cancer Suppl 7:78
Borst J, Griend RJ van de, Oostveen JW van, Ang S-W, Melief CJ, Seidman JG, Bis RLH (1987) A T cell receptor γ/CD3 complex found on cloned functional lymphocytes. Nature 325:683
Brissinck J, Demanet C, Moser M, Leo O, Thielemans K (1991) Treatment of mice bearing BCL1 lymphoma with bispecific antibodies. J Immunol 147:4019
Britton KE (1990) The development of new radiopharmaceuticals Eur J Nucl Med 16:373
Byers VS, Baldwin RW (1991) Rationale for clinical use of immunotoxin in cancer and autoimmune disease. Semin Cell Biol 2:59
Cherwinski HM, Schumacher JH, Brown KD, Mosmann TR (1987) Two types of mouse helper T cell clone. III. Further diffrences in lymphokin synthesis between Th1 and Th2 clones revealed by RNA hybridization, functionally monospecific bioassays and monoclonal antibodies. J Exp Med 166:1229
Demanet C, Brissinck J, Van Mechelen M, Leo O, Thielemans K (1991) Treatment of murine B cell lymphoma with bispecific monoclonal antibodies (anti-idiotype × anti-CD3). J Immunol 147:1091
Epstein AL, Khawli LA (1991) Tumor biology and monoclonal antibodies: overview of basic principles and clinical considerations. Antibody Immunoconjugates Radiopharm 4:373
Ferrini S, Progione I, Mammoliti S, Colnaghi MI, Menard S Moretta A, Moretta L (1989) Re-targeting of human lymphocytes expressing the T cell receptor gamma/delta to ovarian carcinoma cells by the use of bispecific monoclonal antibodInt. J Cancer 44:245
Garrido MA, Perez P, Titus JA, Valdayo MJ, Winkler DF, Barbieri SA, Wunderlich JR, Segal DM (1990) Targeted cytotoxic cells in human peripheral blood lymphocytes. J Immunol 44:2891
Reference deleted
Hendrix PG, Hoylaerts MF, Nouwen EJ, De Broe ME (1990) Enzyme immunoassay of human placental and germ-cell alkaline phosphatase in serum. Clin Chem 36:1793
Herlyn D, Koprowski H (1982) IgG2a monoclonal antibodies inhibit human tumor growth through interaction with effector cells. Proc Natl Acad Sci USA 79:4761
Hoogenboom HR, Raus JC, Volckaert G (1991) Targeting of tumor necrosis factor to tumor cells: secretion by myeloma cells of a genetically engineered antibody-tumor necrosis factor hybrid molecule. Biochim Biophys Acta 1096:345
Ite JP, Janeway CA (1984) Cloned helper T cells can kill B lymphoma cells in the presence of specific antigen: Ia restriction and cognate vs noncognate interactions in cytolysis. Eur J Immunol 14:878
Kim JA, Woods A, Becker-Dunn E, Bottomly K (1985) Distinct functional phenotypes of cloned Ia-restricted helper T cells. J Exp Med 162:188
Kipps TJ, Farham P, Punt J, Herzenberg L (1985) Importance of immunoglobulin isotype in human antibody-dependent cell-mediated cytotoxicity directed by murine moncolonal antibodies. J Exp Med 161:1
Lanzavecchia A, Scheidegger D (1987) The use of hybrid hybridomas to target human cytotoxic T lymphocytes. Eur J Immunol 17:105
Larson SM (1990) Clinical radioimmunodetection, 1978–1988: overview and suggestions for standardization of clinical trials. Cancer Res 50 [Suppl 3]:892
Mazzocchi A, Anichini A, Castelli C, Sensi M, Poli F, Russo C, Parmiani G (1990) T lymphocytes can mediate lysis of autologous melanoma cells by multiple mechanisms: evidence with a single T cell clone. Cancer Immunol Immunother 32:13
Nitta T, Sato K, Yagita H, Okumura K, Ishü S (1990) Preliminary trial of specific targeting therapy against malignant glioma. Lancet 335:368
Oldham RK (1991) Custom-tailored drug immunoconjugates in cancer therapy. Mol Biother 3:148
Perez P, Titus JA, Lotze MT, Cuttitta F, Longo DL, Groves ES, Rabin H, Durda PJ, Segal DM (1986) Specific lysis of human tumor cells by T cells coated with anti-T3 cross-linked to antitumor antibody. J Immunol 137:2069
Qian J, Titus JA, Andrew SM, Mezzanzanica D, Garrido MA, Wunderlich JR, Segal DM (1991) Human PBL targeted with bispecific antibodies release, cytokines that are essential for inhibiting tumor growth. J Immunol 146:3250
Shih LB, Xuan H, Sharkey RM, Goldenberg DM, (1990) A fluorouridine-anti-CEA immunoconjugate is therapeutically effective in a human colonic cancer xenograft model. Int J Cancer 15:1101
Smans KA, Hoylaerts MF, Hendrickx HF, Goergen MJ, De Broe ME (1991) Tumor cell lysis by in-situ activated human peripheralblood mononuclear cells. Int J Cancer 47:431
Stevensen GT, Glennie MJ (1980) Surface immunoglobulin of B-lymphocytic tumors as a therapeutic agent. Cancer Surv 4:213
Van Dijk J, Warnaar SO, Van Eendenburg JDH, Thienpont M, Braakman E, Boot JHA, Flueren FJ, Bolhuis RLH (1989) Induction of tumor-cell lysis by bi-specific monoclonal antibodies recognizing renal-cell carcinoma and CD3 antigen. Int J Cancer 43:344
Van Wauwe JP, De Mey JR, Goossens JG (1980) OKT3: a monoclonal anti-human T-lymphocyte antibody with potent mitogenic properties. J Immunol 124:2708
Wawrzynczak EJ (1991) Systemic immunotoxin therapy of cancer: advances and prospects. Br J Cancer 64:624
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Smans, K.A., Hoylaerts, M.F. & De Broe, M.E. Requirement of monocytes and T-helper cells during development of tumor cell cytotoxicity in targeted T cells. Cancer Immunol Immunother 38, 43–52 (1994). https://doi.org/10.1007/BF01517169
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF01517169