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. 1997 Oct;45(1):20–28. doi: 10.1007/s002620050396

Taxol-mediated changes in fibrosarcoma-induced immune cell function: Modulation of antitumor activities

David W Mullins 1, Thomas M Walker 1, Carol J Burger 1, Klaus D Elgert 1,✉
PMCID: PMC11037653  PMID: 9353423

Abstract

The anticancer drug taxol (paclitaxel) inhibits tumors through multiple cytotoxic and cytostatic mechanisms. Independently of these mechanisms, taxol induces distinct immunological efficacy when it acts as a second signal for activation of tumoricidal activity by interferon-γ(IFNγ)-primed murine normal host macrophages. We reported that tumor-distal macrophages, which mediate immunosuppression through dysregulated nitric oxide (NO) and tumor necrosis factor α (TNFα) production, are differentially regulated by taxol. Because taxol influences tumor cell growth dynamics and activates immune cell populations, we assessed the ex vivo immunosuppressive and antitumor activities of taxol-treated normal host and tumor-bearing host (TBH) macrophages. Pretreatment of such cells with taxol partly reconstituted T cell alloantigen reactivity, suggesting that taxol mediates a limited reversal of TBH macrophage immunosuppressive activity. Taxol-treated TBH macrophages significantly suppressed the growth of fibrosarcoma cells (Meth-KDE) through soluble effector molecules and promoted direct cell-mediated cytotoxicity, indicating that taxol enhanced tumor-induced macrophage antitumor activities. Tumor-induced helper T cells, however, showed a higher sensitivity to direct taxol-induced suppression. These data demonstrate that taxol exerts pleiotropic effects on antitumor immune responses with the capacity to abate the immunosuppressive activities of macrophages and promote macrophage-mediated anti-tumor activities simultaneously, but also directly modulating T cell reactivity. Collectively, these studies suggest that the antineoplastic drug taxol may impart antitumor activity through an immunotherapeutic capacity.

Key words: Taxol, Macrophages, T lymphocytes, Cytotoxicity, Immunotherapy

References

  • 1.Ahmed SA, Gogal RM, Walsh JE. A new rapid and simple non-radioactive assay to monitor and determine the proliferation of lymphocytes: an alternative to [3H]thymidine incorporation assays. J Immunol Methods. 1994;171:211–211. doi: 10.1016/0022-1759(94)90396-4. [DOI] [PubMed] [Google Scholar]
  • 2.Albina JE, Abate JA, Henry WL. Nitric oxide production is required for murine resident peritoneal macrophages to suppress mitogen-stimulated T cell proliferation: role of IFN-γ in the induction of the nitric oxide-synthesizing pathway. J Immunol. 1991;147:144–144. [PubMed] [Google Scholar]
  • 3.Alleva DG, Burger CJ, Elgert KD. Tumor-induced regulation of suppressor macrophage nitric oxide and TNF-oc production: role of tumor-derived IL-10, TGF-β, and prostaglandin E2 . J Immunol. 1994;153:1674–1674. [PubMed] [Google Scholar]
  • 4.Beissert S, Bergholz M, Waase I, Lepsien G, Schauer A, Pfizenmaier K, Kronke M. Regulation of tumor necrosis factor gene expression in colorectal adenocarcinoma: in vivo analysis by in situ hybridization. Proc Natl Acad Sci USA. 1989;86:5064–5064. doi: 10.1073/pnas.86.13.5064. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Bhalla K, Ibrado AM, Tourkina E, Tang C, Mahoney ME, Huang Y. Taxol induces internucleosomal DNA fragmentation associated with programmed cell death in human myeloid leukemia cells. Leukemia. 1993;7:563–563. [PubMed] [Google Scholar]
  • 6.Bogdan C, Ding A. Taxol, a microtubule-stabilizing antineoplastic agent, induces expression of tumor necrosis factor-α and interleukin-1 in macrophages. J Leukoc Biol. 1992;52:119–119. doi: 10.1002/jlb.52.1.119. [DOI] [PubMed] [Google Scholar]
  • 7.Bottex-Gauthier C, Condemine F, Picot F, Vidal D. Effects of taxol on the macrophage function: interactions with some immunological parameters. Immunopharmacol Immunotoxicol. 1992;14:39–39. doi: 10.3109/08923979209009212. [DOI] [PubMed] [Google Scholar]
  • 8.Brown DL, Little JE, Chaly N, Schweitzer I, Paulin-Levasseur M. Effects of taxol on microtubule organization in mouse splenic lymphocytes and on response to mitogenic stimulation. Eur J Cell Biol. 1985;37:130–130. [PubMed] [Google Scholar]
  • 9.Chuang LT, Lotzova E, Cook KR, Cristoforoni P, Morris M, Wharton JT. Effect of new investigational drug taxol on oncolytic activity and stimulation of human lymphocytes. Gynecol Oncol. 1993;49:291–291. doi: 10.1006/gyno.1993.1129. [DOI] [PubMed] [Google Scholar]
  • 10.Chuang LT, Lotzova E, Heath J, Cook KR, Munkarah A, Morris M, Wharton JT. Alteration of lymphocyte microtubule assembly, cytotoxicity, and activation by the anticancer drug taxol. Cancer Res. 1994;54:1286–1286. [PubMed] [Google Scholar]
  • 11.Denis M. Human monocytes/macrophages: NO or no NO? J Leukoc Biol. 1994;55:682–682. doi: 10.1002/jlb.55.5.682. [DOI] [PubMed] [Google Scholar]
  • 12.Ding AH, Porteu F, Sanchez E, Nathan CF. Shared actions of endotoxin and taxol on TNF receptors and TNF release. Science. 1990;248:370–370. doi: 10.1126/science.1970196. [DOI] [PubMed] [Google Scholar]
  • 13.Donaldson KL, Goolsby GL, Wahl AF. Cytotoxicity of the anticancer agents cisplatin and taxol during cell proliferation and the cell cycle. Int J Cancer. 1994;57:847–847. doi: 10.1002/ijc.2910570614. [DOI] [PubMed] [Google Scholar]
  • 14.Dugas B, Mossalayi MD, Damais C, Kolb J-P. Nitric oxide production by human monocytes: evidence for role of CD23. Immunol Today. 1995;16:574–574. doi: 10.1016/0167-5699(95)80080-8. [DOI] [PubMed] [Google Scholar]
  • 15.Eisenstein TK. Suppressor macrophages. Immunol Ser. 1994;60:203–203. [PubMed] [Google Scholar]
  • 16.Elgert KD, Connolly KM. Macrophage regulation of the T cell allogeneic response during tumor growth. Cell Immunol. 1978;35:1–1. doi: 10.1016/0008-8749(78)90121-1. [DOI] [PubMed] [Google Scholar]
  • 17.Elgert KD, Farrar WL. Suppressor cell activity in tumor-bearing mice. I. Dualistic inhibition by suppressor T lymphocytes and macrophages. J Immunol. 1978;120:1345–1345. [PubMed] [Google Scholar]
  • 18.Fuchs DA, Johnson RK. Cytologic evidence that taxol, an antineoplastic agent from Taxus brevifolia, acts as a mitotic spindle poison. Cancer Treat Rep. 1978;62:1219–1219. [PubMed] [Google Scholar]
  • 19.Green LC, Wagner DA, Glogowski J, Skipper PL, Wishnok JS, Tannenbaum SR. Analysis of nitrate, nitrite, [15N]nitrate in biological fluids. Anal Biochem. 1982;126:131–131. doi: 10.1016/0003-2697(82)90118-X. [DOI] [PubMed] [Google Scholar]
  • 20.Gregory SH, Sagnimeni AJ, Wing EJ. Arginine analogues suppress antigen-specific and -nonspecific T lymphocyte proliferation. Cell Immunol. 1994;153:527–527. doi: 10.1006/cimm.1994.1048. [DOI] [PubMed] [Google Scholar]
  • 21.Hajek R, Vorlicek J, Slavik M. Paclitaxel (taxol): a review of its antitumor activity in clinical studies. Neoplasma. 1996;43:141–141. [PubMed] [Google Scholar]
  • 22.Hibbs JB, Taintor RR, Vavrin Z, Rachlin EM. Nitric oxide: a cytotoxic activated macrophage effector molecule. Biochem Biophys Res Commun. 1988;157:87–87. doi: 10.1016/S0006-291X(88)80015-9. [DOI] [PubMed] [Google Scholar]
  • 23.Holmes FA, Walters RS, Theriault RL, Forman AD, Newton LK, Raber MN, Buzdar AU, Frye DK, Hortobagyi GN. Phase II trial of taxol, an active drug in the treatment of metastatic breast cancer. J Natl Cancer Inst. 1991;83:1797–1797. doi: 10.1093/jnci/83.24.1797-a. [DOI] [PubMed] [Google Scholar]
  • 24.Hwang S, Ding A. Activation of NF-kappa B in murine macrophages by taxol. Cancer Biochem Biophys. 1995;14:265–265. [PubMed] [Google Scholar]
  • 25.Kingston DGI. The chemistry of taxol. Pharmacol Ther. 1991;52:1–1. doi: 10.1016/0163-7258(91)90085-Z. [DOI] [PubMed] [Google Scholar]
  • 26.Kirikae T, Ojima I, Kirikae F, Ma Z, Kuduk SD, Slater JC, Takeuchi CS, Bounaud PY, Nakano M. Structural requirements of taxoids for nitric oxide and tumor necrosis factor production by murine macrophages. Biochem Biophys Res Commun. 1996;227:227–227. doi: 10.1006/bbrc.1996.1494. [DOI] [PubMed] [Google Scholar]
  • 27.Liebmann J, Cook JA, Fisher J, Teague D, Mitchell JB. In vitro studies of taxol as a radiation sensitizer in human tumor cells. J Natl Cancer Inst. 1994;86:441–441. doi: 10.1093/jnci/86.6.441. [DOI] [PubMed] [Google Scholar]
  • 28.Manfredi JJ, Horwitz SB. Taxol: an antimitotic agent with a new mechanism of action. In: Dethlefsen LA, editor. International encyclopedia of pharmacology and therapeutics, cell cycle effects of drugs, vol 121. Oxford: Pergamon; 1986. pp. 287–333. [Google Scholar]
  • 29.Manfredi JJ, Parness J, Horwitz SB. Taxol binds to cellular microtubules. J Cell Biol. 1982;94:688–688. doi: 10.1083/jcb.94.3.688. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Manthey CL, Brandes ME, Perera P-Y, Vogel SN. Taxol increases steady-state levels of lipopolysaccharide-inducible genes and protein-tyrosine phosphorylation in murine macrophages. J Immunol. 1992;149:2459–2459. [PubMed] [Google Scholar]
  • 31.Manthey CL, Perera P-Y, Salkowski CA, Vogel SN. Taxol provides a second signal for murine macrophage tumorcidical activity. J Immunol. 1994;152:825–825. [PubMed] [Google Scholar]
  • 32.Mantovani A, Ming WJ, Batotta C, Abdeljali B, Botazzi B. Origin and regulation of tumor-associated macrophages: the role of tumor-derived chemotactic factor. Biochim Biophys Acta. 1986;865:59–59. doi: 10.1016/0304-419x(86)90013-2. [DOI] [PubMed] [Google Scholar]
  • 33.McGuire WP, Rowinsky EK, Rosenshein NB, Grumbine FC, Ettinger DS, Armstrong DK, Donehower RC. Taxol: a unique antineoplastic agent with significant activity in advanced ovarian epithelial neoplasms. Ann Int Med. 1989;111:273–273. doi: 10.7326/0003-4819-111-4-273. [DOI] [PubMed] [Google Scholar]
  • 34.Mills CD, Shearer J, Evans R, Caldwell MD. Macrophage arginine metabolism and the inhibition or stimulation of cancer. J Immunol. 1992;149:2709–2709. [PubMed] [Google Scholar]
  • 35.Moncada S, Palmer RMJ, Hibbs EA. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev. 1991;43:109–109. [PubMed] [Google Scholar]
  • 36.Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxic assays. J Immunol Methods. 1983;65:55–55. doi: 10.1016/0022-1759(83)90303-4. [DOI] [PubMed] [Google Scholar]
  • 37.Mullins DW, Alleva DG, Burger CJ, Elgert KD (1997) Taxol, a microtubule-stabilizing antineoplastic agent, differentially regulates normal and tumor-bearing host macrophage nitric oxide production. Immunopharmacology (in press) [DOI] [PubMed]
  • 38.Ozols RF. Current status of chemotherapy for ovarian cancer. Semin Oncol. 1995;22:61–61. [PubMed] [Google Scholar]
  • 39.Rowinsky EK, Donehower RC, Jones RJ, Tucker RW. Microtubule changes and cytotoxicity in leukemic cell lines treated with taxol. Cancer Res. 1988;48:4093–4093. [PubMed] [Google Scholar]
  • 40.Roy C, Chaly N, Brown DL. Taxol-induced reorganization of the microtubule system in murine splenic lymphocytes inhibits response to allogeneic cells but not to concanavalin A. Biochem Cell Biol. 1988;66:389–389. doi: 10.1139/o88-047. [DOI] [PubMed] [Google Scholar]
  • 41.Russell SW, Pace JL, Varesio L, Akporiaya E, Blasi E, Celando A, Schreiber RD, Schultz RM, Stevenson AP, Stewart CC, Stewart SJ. Comparison of five short-term assays that measure nonspecific cytotoxicity mediated to tumor cells by activated macrophages. J Leukoc Biol. 1986;40:801–801. doi: 10.1002/jlb.40.6.801. [DOI] [PubMed] [Google Scholar]
  • 42.Schiff PB, Fant J, Horwitz SB. Promotion of microtubule assembly in vitro by taxol. Nature. 1979;22:665–665. doi: 10.1038/277665a0. [DOI] [PubMed] [Google Scholar]
  • 43.Vogel SN, Manthey CL, Brandes ME, Perera P-Y, Salkowski CA. LPS minetic effects of taxol on LPS-inducible gene expression, glucorticoid receptor expression, and tyrosine phosphorylation in murine macrophages. In: Levin J, Alving CR, Munford RS, Stutz PL, editors. Bacterial endotoxin: recognition and effector mechanisms. New York: Excerpta Medica; 1993. pp. 243–243. [Google Scholar]
  • 44.Walker TM, Burger CJ, Elgert KD. Tumor growth alters T cell and macrophage production of and responsiveness to granulocyte-macrophage colony-stimulating factor: partial dysregulation through interleukin-10. Cell Immunol. 1994;154:342–342. doi: 10.1006/cimm.1994.1082. [DOI] [PubMed] [Google Scholar]
  • 45.Weinberg JB, Misukonis MA, Shami PJ, Mason SN, Sauls DL, Dittman WA, Wood ER, Smith GK, McDonald B, Bachus KE, Haney AF, Granger DL. Human mononuclear phagocyte inducible nitric oxide synthase (iNOS): analysis of iNOS mRNA, iNOS protein, biopterin, and nitric oxide production by blood monocytes and peritoneal macrophages. Blood. 1995;86:1184–1184. [PubMed] [Google Scholar]
  • 46.Williams S, Mutch DG, Xu L, Collins JL. Divergent effects of taxol on tumor necrosis factor-α-mediated cytolysis of ovarian carcinoma cells. Am J Obstet Gynecol. 1992;167:1870–1870. doi: 10.1016/0002-9378(92)91789-d. [DOI] [PubMed] [Google Scholar]
  • 47.Yurochko AD, Burger CJ, Elgert KD. Tumor modulation of autoreactivity: decreased macrophage and autoreactive T cell interactions. Cell Immunol. 1990;127:105–105. doi: 10.1016/0008-8749(90)90118-B. [DOI] [PubMed] [Google Scholar]

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