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. 1989 May;30(3):158–164. doi: 10.1007/BF01669424

Effect of indomethacin on tumor-infiltrating lymphocytes of a spontaneously developed murine mammary adenocarcinoma

Tsu-Yi Chao 1, T Ming Chu 1,✉
PMCID: PMC11038696  PMID: 2598184

Abstract

The effect of indomethacin on tumor-infiltrating lymphocytes (TIL) was investigated in a spontaneously developed and weakly immunogenic murine mammary adenocarcinoma (designated JC) in syngeneic immunocompetent BALB/c mice, a tumor model mimicking human disease. Unlike other chemically and virally induced tumors, the expansion of TIL was only possible with an enriched population of lymphocytes, isolated on a discontinuous density gradient then cultured in complete medium containing recombinant human interleukin-2 (rIL-2). The freshly isolated TIL exhibited no cytotoxicity against either the natural-killer-sensitive YAC-1 or the natural-killer-resistant JC cell lines. After culture in rIL-2, the TIL of the JC tumor lysed both YAC-1 and JC. The cytotoxicity of the TIL reached a maximum between the 2nd and 3rd week of culture and decreased thereafter. Antibody-and complement-depletion tests revealed that the cells bearing asialo-GM1 antigen represented the major precursor cells of the cytotoxic TIL, which may explain its nonspecific cytotoxicity. Indomethacin was shown to accelerate the cell proliferation of the rIL-2-activated TIL, but only in the initial 2 weeks of culture and not in later culture. The addition of indomethacin to the rIL-2-containing medium at the beginning of culture resulted in a fast-acting and long-lasting enhancement in cytotoxicity. These results provided a basis for the clinical use of indomethacin, i.e. acceleration in proliferation and augmentation in cytotoxicity. However, the addition of indomethacin at the end of the fourth week after rIL-2 culturing produced neither accelerated proliferation nor augmented cytotoxicity. This study also suggested that a prolonged administration of indomethacin may not be advantageous in clinical trials, since the long-term continuous presence of indomethacin in the culture has resulted in a negative effect on the growth of TIL.

Keywords: Indomethacin, Human Disease, Density Gradient, Precursor Cell, Tumor Model

References

  • 1.Anderson TM, Ibayashi Y, Holmes EC, Golub SH. Modification of natural killer activity of lymphocytes infiltrating human lung cancers. Cancer Immunol Immunother. 1987;25:65. doi: 10.1007/BF00199303. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Anderson TM, Ibayashi Y, Takuda Y, Colquhoun SD, Holmes EC, Golub SH. Effects of systemic recombinant interleukin-2 on natural killer and lymphokine activated killer activity of human tumor infiltrating lymphocytes. Cancer Res. 1988;48:1180. [PubMed] [Google Scholar]
  • 3.Bayer BM, Beaven MA. Evidence that indomethacin reversibly inhibits cell growth in the G1 phase of the cell cycle. Biochem Pharmacol. 1979;28:441. doi: 10.1016/0006-2952(79)90112-6. [DOI] [PubMed] [Google Scholar]
  • 4.Belldegrun A, Muul LM, Rosenberg SA. Interleukin 2 expanded tumor-infiltrating lymphocytes in human renal cell cancer: isolation, characterization and antitumor activity. Cancer Res. 1988;48:206. [PubMed] [Google Scholar]
  • 5.Brunda MJ, Herberman RB, Holden HT. Inhibition of murine natural killer cell activity by prostaglandins. J Immunol. 1980;124:2682. [PubMed] [Google Scholar]
  • 6.Capone PM, Kadohama N, Chu TM. Immunotherapy in a spontaneously developed murine mammary carcinoma with syngeneic monoclonal antibody. Cancer Immunol Immunother. 1987;25:93. doi: 10.1007/BF00199947. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Chao TY, Chu TM (1989) Characterization of a new spontaneously developed murine mammary adenocarcinoma in syngeneic BALB/c hosts. In Vitro Cell Dev Biol (in press) [DOI] [PubMed]
  • 8.Crout E, Hepburn B, Ritts RE., Jr Suppression of lymphocyte transformation after aspirin ingestion. New Engl J Med. 1975;292:221. doi: 10.1056/NEJM197501302920501. [DOI] [PubMed] [Google Scholar]
  • 9.Doyle MV, Lee MT, Fong S. Comparison of the biological activities of human recombinant interleukin-2125 and native interleukin-2. J Biol Response Mod. 1985;4:96. [PubMed] [Google Scholar]
  • 10.Goodwin JS, Webb DR. Regulation of the immune response by prostaglandins. Clin Immunol Immunopathol. 1980;15:106. doi: 10.1016/0090-1229(80)90024-0. [DOI] [PubMed] [Google Scholar]
  • 11.Heo DS, Whiteside TL, Kanbour A, Herberman RB. Lymphocytes infiltrating human ovarian tumor. I. Role of Leu-19(NKH1)-positive recombinant IL-2-activated culture of lymphocytes infiltrating human ovarian tumors. J Immunol. 1988;140:4042. [PubMed] [Google Scholar]
  • 12.Lala PK, Parhar RS. Cure of B16F10 melanoma lung metastasis in mice by chronic indomethacin therapy combined with repeated rounds of interleukin-2: characteristics of killer cells generated in situ. Cancer Res. 1988;48:1072. [PubMed] [Google Scholar]
  • 13.Lala PK, Parhar RS, Singh P. Indomethacin therapy abrogates the prostaglandin-mediated suppression of natural killer activity in tumor bearing mice and prevents tumor metastasis. Cell Immunol. 1986;99:108. doi: 10.1016/0008-8749(86)90220-0. [DOI] [PubMed] [Google Scholar]
  • 14.McCormick KJ, Panje WR. Indomethacin-induced augmentation of lymphoproliferative responses in patients with head and neck cancer. Cancer Immunol Immunother. 1986;21:226. doi: 10.1007/BF00199366. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Miescher S, Whiteside TL, Carrel S, von Fliedner V. Functional properties of tumor infiltrating and blood lymphocytes in patients with solid tumors: Effects of tumor cells and their supernatants on proliferative responses of lymphocytes. J Immunol. 1986;136:1899. [PubMed] [Google Scholar]
  • 16.Muul LM, Spiess PJ, Director EP, Rosenberg SA. Identification of specific cytolytic immune responses against autologous tumor in humans bearing malignant melanoma. J Immunol. 1987;138:989. [PubMed] [Google Scholar]
  • 17.Murray JL, Dowd J, Hersh EM. In vitro inhibition of interleukin-2 production by peripheral blood lymphocytes from stage III melanoma patients by prostaglandin E2: enhancement of lymphocyte proliferation by exogenous interleukin-2 plus indomethacin. J Biol Response Mod. 1986;5:12. [PubMed] [Google Scholar]
  • 18.Nishimura T, Yagi H, Uchiyama Y, Hashimoto Y. Generation of lymphokine-activated killer (LAK) cells from the tumor-infiltrating lymphocytes. Cell Immunol. 1986;100:149. doi: 10.1016/0008-8749(86)90015-8. [DOI] [PubMed] [Google Scholar]
  • 19.Opelz G, Terasaki PI. Suppression of lymphocyte transformation by aspirin. Lancet. 1973;II:478. doi: 10.1016/s0140-6736(73)92073-4. [DOI] [PubMed] [Google Scholar]
  • 20.Radrizzani M, Gambacorti-Passerini C, Parmiani G, Fossati G. Lysis by interleukin-2 stimulated tumor-infiltrating lymphocytes of autologus and allogeneic tumor target cells. Cancer Immunol Immunother. 1989;28:67. doi: 10.1007/BF00205803. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Rosenberg SA, Grimm EA, McCrogan M, Doyle MV, Kawasaki E, Koths K, Mark DF. Biological activity of recombinant interleukin-2 produced inEscherichia coli . Science. 1983;223:1412. doi: 10.1126/science.6367046. [DOI] [PubMed] [Google Scholar]
  • 22.Rosenberg SA, Spiess P, Lafreniere R. A new approach to the adoptive immunotherapy of cancer with tumor-infiltrating lymphocytes. Science. 1986;233:1318. doi: 10.1126/science.3489291. [DOI] [PubMed] [Google Scholar]
  • 23.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. 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. New Engl J Med. 1987;316:889. doi: 10.1056/NEJM198704093161501. [DOI] [PubMed] [Google Scholar]
  • 24.Spiess PJ, Yang JC, Rosenberg SA. In vivo antitumor activity of tumor-infiltrating lymphocytes expanded in recombinant interleukin-2. J Natl Cancer Inst. 1987;79:1067. [PubMed] [Google Scholar]
  • 25.von Kleist S, Berling J, Bohle W, Wittekind C. Immunohistological analysis of lymphocyte subpopulations infiltrating breast carcinomas and benign lesions. Int J Cancer. 1987;40:18. doi: 10.1002/ijc.2910400105. [DOI] [PubMed] [Google Scholar]
  • 26.Wang A, Lu SD, Mark D. Site-specific mutagenesis of the human interleukin-2 gene: structure-function analysis of cysteine residues. Science. 1984;222:1431. doi: 10.1126/science.6427925. [DOI] [PubMed] [Google Scholar]
  • 27.Wei W, Heppner GH. Tumor infiltrating lymphocytes of spontaneous versus transplanted mouse mammary tumors. Cancer Immunol Immunother. 1988;26:257. doi: 10.1007/BF00199938. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.West WH, Tauer KW, Yannelli JR, Marshall GD, Orr DW, Thruman GB, Oldham RK. Constant-infusion recombinant-interleukin-2 in adoptive immunotherapy of advanced cancer. New Engl J Med. 1987;316:898. doi: 10.1056/NEJM198704093161502. [DOI] [PubMed] [Google Scholar]
  • 29.Whiteside TL, Miescher S, Hurlimann J, Moretta L, von Fliedner V. Clonal analysis and in situ characterization of lymphocytes infiltrating human breast carcinomas. Cancer Immunol Immunother. 1986;23:169. doi: 10.1007/BF00205646. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Whiteside TL, Miescher S, MacDonald HR, von Fliedner V. Separation of tumor-infiltrating lymphocytes from tumor cells in human solid tumors. A comparison between velocity sedimentation and discontinuous density gradients. J Immunol Methods. 1986;90:221. doi: 10.1016/0022-1759(86)90079-7. [DOI] [PubMed] [Google Scholar]

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