Abstract
Interleukin-2 plays a crucial role in enhancing the antitumor immune response. Clinical trials, mainly in renal cell carcinoma and melanoma patients, have been carried out with encouraging results. Recent reports demonstrated that interleukin-2 therapy may depress the immune response either in vitro or in vivo. We decided to monitor, in nine renal cancer patients, the proliferative responses and the parallel variations in Ca2+ homeostasis of peripheral blood lymphocytes collected before, during and after the first cycle of a 3-day interleukin-2 systemic administration. The proliferative response to phytohemagglutinin or concanavalin A significantly dropped early during interleukin-2 infusion. Consistently, an impairment in mobilizing Ca2+, either from internal stores or via influx from outside, was observed. Results obtained with a mAb-αCD3 molecular complex strongly suggested that the TCR/CD3 signal transduction pathway was defective. In contrast, no major variations were observed in the general machinery controlling Ca2+ homeostasis nor in the total Ca2+-releasable pool. Patients' lymphocytes, cultured in vitro for 3 days in medium alone, showed an almost complete recovery in their ability to respond to mitogens. In conclusion, we show that interleukin-2 administration in cancer patients induces a reversible state of anergy in circulating lymphocytes, assessed both by the reduction in the proliferative response and the block of the mitogen-activated intracellular Ca2+ signalling.
Similar content being viewed by others
References
Ades EW, Bosse D, Orr S, Gillespie T (1990) Immune, responses in humans while receiving adoptive immunotherapy with recombinant interleukin-2 and lymphokine-activated killer cells: acute anergy to mitogens and recall antigens. Pathobiology 58: 78
Boccoli G, Masciulli R, Ruggeri EM, Carlini P, Giannella G, Montesoro E, Mastroberardino G, Isacchi G, Testa U, Calabresi, F, Peschle C (1990) Adoptive immunotherapy of human cancer: the cytokine cascade and monocyte activation following high-dose interleukin-2 bolus treatment. Cancer Res 50: 5795
Clementi E, Scheer H, Zacchetti D, Fasolato C, Pozzan T, Meldolesi J (1992) Receptor-activated Ca2+ influx. J Biol Chem 267: 2164
Fasolato C, Zottini M, Clementi E, Zacchetti D, Meldolesi J, Pozzan T (1991) Intracellular Ca2+ pools in PC12 cells. J Biol Chem 266: 20159
Fortis C, Ferrero E, Besana C, Biffi M, Heltai S, Galli L, Borri A, Schoenheit A, Rugarli C (1990) Recombinant interleukin-2 and lymphokine-activated killer cells in renal cancer patients. I. Phenotypic and functional analysis of the peripheral blood mononuclear cells. Cancer Immunol Immunother 32: 161
Fortis C, Ferrero E, Heltai S, Besana C, Corti C, Di Lucca G, Foppoli M, Consogno G,. Rugarli C (1993) Role of interleukin-2 in regulating lymphocyte activation and recirculation. Eur J Cancer 29A: 474
Grossman Z, Paul WE (1992) Adaptive cellular interactions in the immune system: the tunable activation threshold and the significance of subthreshold responses. Proc Natl Acad Sci USA 89: 10365
Grynkiewicz G, Poenie M, Tsien RY (1985) A new generation of Ca2+ indicators with greatly improved fluorescence properties. J Biol Chem 260: 3440
Guse AH, Roth E, Emmrich F (1993) Intracellular Ca2+ pools in Jurkat T-lymphocytes. Biochem J 291: 447
Hank JA, Sosman JA, Kohler PC, Bechhofer R, Storer B, Sondel PM (1990) Depressed in vitro T cell responses concomitant with augmented interleukin-2 responses by lymphocytes from cancer patients following in vivo treatment with interleukin-2. J Biol Response Mod 9: 5
Isakov N, Scholz W, Altman A (1986) Signal transduction and intracellular events in T-lymphocyte activation. Immunol Today 7: 271
Kasid A, Director EP, Rosenberg SA (1989) Induction of endogenous cytokine-mRNA in circulating peripheral blood mononuclear cells by IL-2 administration to cancer patients. J Immunol 143: 736
LaSalle JM, Tolentino PJ, Freeman GJ, Nadler LM, Hafler DA (1992) Early signaling defects in human T cell anergized by T cell presentation of autoantigen. J Exp Med 176: 177
Lenardo MJ (1991) Interleukin-2 programs mouse αβ T lymphocytes for apoptosis. Nature 353: 858
Mizoguchi H, O'Shea JJ, Longo DL, Loeffler CM, McVicar DW, Ochoa AC (1992) Alterations in signal transduction molecules in T lymphocytes from tumor-bearing mice. Science 258: 1795
O'Flynn K, Knott LJ, Russul-Saib M, Abdul-Gaffar R, Morgan G, Beverley PCL, Linch DC (1986) CD2 and CD3 antigens mobilize Ca2+ independently. Eur J Immunol 16: 580
Parmiani G (1990) An explanation of the variable clinical response to interleukin-2 and LAK cells. Immunol Today 11: 113
Rosenthal NS, Hank JA, Kohler PC, Minkoff DZ, Moore KH, Bechhofer R, Hong R, Storer B, Soudel PM (1988) The in vitro function of lymphocytes from 25 cancer patients receiving four to seven consecutive days of recombinant IL.-2. J Biol Response Mod 7: 123
Schwartz RH (1990) A cell culture model for T lymphocyte clonal anergy. Science 248: 1349
Weil-Hillman G, Hank JA, Rosenthal NS, Sondel P (1988) Transient decrease in IL-2-responsive lymphocytes 24 hours after initiation of continuous IL-2 infusion in cancer patients. J Biol Response Mod 7: 424
Wiebke EA, Rosenberg SA, Lotze MT (1988) Acute immunologic effects of interleukin-2 therapy in cancer patients: decreased delayed type hypersensivity response and decreased proliferative response to soluble antigens. J Clin Oncol 6: 1440
Zweifach A, Lewis RS (1993) Mitogen-regulated Ca2+ current of T lymphocytes is activated by depletion of intracellular Ca2+ stores. Proc Natl Acad Sci USA 90: 6295
Author information
Authors and Affiliations
Additional information
This work was supported by grant CNR-ACRO 9202374
Rights and permissions
About this article
Cite this article
Clementi, E., Bucci, E., Citterio, G. et al. Reversible anergy in circulating lymphocytes of cancer patients during interleukin-2 therapy. Cancer Immunol Immunother 39, 167–171 (1994). https://doi.org/10.1007/BF01533382
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF01533382