Skip to main content
Cancer Immunology, Immunotherapy : CII logoLink to Cancer Immunology, Immunotherapy : CII
. 1993 Mar;36(2):115–122. doi: 10.1007/BF01754411

The influence of cyclophosphamide on antitumor immunity in mice bearing late-stage tumors

Filip Čulo 1,, Ivica Klapan 2, Toni Kolak 1
PMCID: PMC11038762  PMID: 8093855

Abstract

Spleen cells from mice bearing late-stage methylcholanthrene-induced tumor did not show any tumor activity when mixed with tumor cells in Winn's assay. Treatment of these mice with cyclophosphamide (CY) induced a tumor-inhibitory activity in spleen, occurring on day 7 after treatment, reaching its maximum on day 11 and disappearing by day 21. This antitumor activity could not be induced in control, tumor-free or T-deficient tumor-bearing mice. CY-induced tumor-inhibitory activity was immunologically specific, and mediated by Thy-1+, L3T4, Ly-2+ cells. Contrary to spleen cells from untreated tumor-bearing mice, spleen cells from CY-treated tumor-bearing mice did not suppress the antitumor activity of immune spleen cells in Winn's assay. However, in contrast to immune spleen cells, CY-induced tumor-inhibitory cells did not manifest antitumor activity when transferred systemically (i. v.) into T-cell-deficient tumor-bearing mice. Even more, spleen cells from CY-pretreated mice, harvested 7–15 days after the drug administration, partially suppressed the antitumor activity of concomitantly transferred spleen cells from specifically immune mice. Nevertheless, CY-pretreated mice manifested concomitant immunity, i.e. these mice exhibited higher resistance to a second inoculum of the same tumor than did nontreated mice or even mice with excised primary tumor.

Key words: Cyclophosphamide, Tumor immunity, Suppressor cells

References

  • 1.Akard LP, Brandt J, Lu L, Jansen J, Hoffman R. Chronic T cell lymphoproliferative disorder and pure red cell aplasia. Further characterization of cell-mediated inhibition of erythropoiesis and clinical response to cytotoxic chemotherapy. Am J Med. 1987;83:1069–1069. doi: 10.1016/0002-9343(87)90943-0. [DOI] [PubMed] [Google Scholar]
  • 2.Awwad M, North RJ. Cyclophosphamide (CY)-facilitated adoptive immunotherapy of a CY-resistant tumor. Evidence of adoptive T-cell mediated immunity by removing suppressor T cell rather than by reducing tumor burden. Immunology. 1988;65:87–87. [PMC free article] [PubMed] [Google Scholar]
  • 3.Awwad M, North RJ. Cyclophosphamide-induced immunologically mediated regression of a cyclophosphamide-resistant murine tumor: a consequence of eliminating precursor L3T4+ suppressor T-cells. Cancer Res. 1989;49:1649–1649. [PubMed] [Google Scholar]
  • 4.Ballas ZK. Lymphokine-activated killer (LAK) cells. J Immunol. 1986;137:2380–2380. [PubMed] [Google Scholar]
  • 5.Carter RH, Drebin JA, Schatten S, Perry LL, Greene MI. Regulation of the immune response to tumor antigens: IX. In vitro Lyt-1+2− cell proliferative responses to cellbound or subcellular tumor antigen. J Immunol. 1983;130:997–997. [PubMed] [Google Scholar]
  • 6.Čulo F, Allegretti N, Marušic M. Lymphotoxic effect of cyclophosphamide in therapy of Ehrlich ascites carcinoma in mice. JNCI. 1977;58:1759–1759. doi: 10.1093/jnci/58.6.1759. [DOI] [PubMed] [Google Scholar]
  • 7.Dent LA, Finlay-Jones JJ. In vivo detection and partial characterization of effector and suppressor cell populations in spleens of mice with large metastatic fibrosarcomas. Br J Cancer. 1985;51:533–533. doi: 10.1038/bjc.1985.76. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Estin CD, Stevenson US, Hellstrom I, Hellstrom KE. Cyclophosphamide potentates the antitumor activity of vp97NY. Cell Immunol. 1989;120:126–126. doi: 10.1016/0008-8749(89)90180-9. [DOI] [PubMed] [Google Scholar]
  • 9.Evans R. Combination therapy by using cyclophosphamide and tumor-sensitized lymphocytes: a possible mechanism of action. J Immunol. 1983;130:2511–2511. [PubMed] [Google Scholar]
  • 10.Fujiwara H, Fukuzawa M, Yoshioka T, Nakajima H, Hamaoka T. The role of tumor-specific Ly1+2− T cells in eradicating tumor cells in vivo: I. Ly1+2− T cells do not necessarily require recruitment of host, cytotoxic T cells precursor for implementation of in vivo immunity. J Immunol. 1984;133:1671–1671. [PubMed] [Google Scholar]
  • 11.Glaser M. Augmentation of specific immune response against a syngeneic SV40-induced sarcoma in mice by depletion of suppressor T cells with cyclophosphamide. Cell Immunol. 1979;48:339–339. doi: 10.1016/0008-8749(79)90128-x. [DOI] [PubMed] [Google Scholar]
  • 12.Greenberg PD, Cheever MA, Fefer A. Eradication of disseminated murine leukemia by chemo-immunotherapy with cyclophosphamide and adoptively transferred immune syngeneic Ly-1+,2− lymphocytes. J Exp Med. 1981;154:952–952. doi: 10.1084/jem.154.3.952. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Greene MI, Perry LL, Benacerraf B. Regulation of the immune response to tumor antigen: V. Modulation of suppressor T-cell activity in vivo. Am J Pathol. 1979;95:159–159. [PMC free article] [PubMed] [Google Scholar]
  • 14.Hellstrom KE, Hellstrom I. Lymphocyte-mediated cytotoxicity and blocking serum activity to tumor antigens. Adv Immunol. 1974;18:209–209. doi: 10.1016/s0065-2776(08)60311-9. [DOI] [PubMed] [Google Scholar]
  • 15.Hengst JCD, Mokyr MB, Dray S. Cooperation between cyclophosphamide tumoricidal activity and host antitumor immunity in the cure of the mice bearing MOPC-315 tumors. Cancer Res. 1981;41:2163–2163. [PubMed] [Google Scholar]
  • 16.Hoon DS, Foshag LJ, Nizze AS, Bohman R, Morton DL. Suppressor cell activity in a randomized trial of patients receiving active specific immunotherapy with melanoma cell vaccine and low dosages of cyclophosphamide. Cancer Res. 1990;50:5358–5358. [PubMed] [Google Scholar]
  • 17.Hoover SK, Barrett SK, Turk TM, Lee TC, Bear HD. Cyclophosphamide and abrogation of tumor-induced suppressor T cell activity. Cancer Immunol Immunother. 1990;31:121–121. doi: 10.1007/BF01742376. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Kawabata TT, White KL., Jr Enhancement of in vivo and in vitro murine immune responses by the cyclophosphamide metabolite acrolein. Cancer Res. 1988;48:41–41. [PubMed] [Google Scholar]
  • 19.Klapan I, Čulo F, Marić M. The influence of cyclophosphamide on tumor-specific immunity. I. Induction of antitumor immunity in mice bearing advanced tumors. Period Biol. 1988;88(Suppl 1A):526–526. [Google Scholar]
  • 20.Lausch RN, Rapp F. Concomitant immunity in hamsters bearing syngeneic transplants of tumors induced by para-adenovirus 7, simian adenovirus 7 or 9,10-dimethylbenzanthracene. Int J Cancer. 1971;7:322–322. doi: 10.1002/ijc.2910070217. [DOI] [PubMed] [Google Scholar]
  • 21.Leclerc JC, Cantor H. T cell-mediated immunity to ocornavirus-induced tumors: II. Ability of different T cell sets to prevent tumor growth in vivo. J Immunol. 1980;124:851–851. [PubMed] [Google Scholar]
  • 22.Loveland BE, McKenzie IPC, Ceredig R. Evidence of different effector T-cell populations for systemic and local immunity. Transplant Proc. 1983;15:347–347. [Google Scholar]
  • 23.Maier T, Holda JH, Claman HN. Murine natural suppressor cells in the newborn, in bone marrow and after cyclophosphamide. Genetic variations and dependence on IFN-gamma. J Immunol. 1989;143(2):491–491. [PubMed] [Google Scholar]
  • 24.Mastrangelo MJ, Schultz S, Kane M, Berd D. Newer immunologic approaches to the treatment of patients with melanoma. Semin Oncol. 1988;15:589–589. [PubMed] [Google Scholar]
  • 25.Mitchell MS, Kempf RA, Harel W, Shau H, Boswell WD, Lind S, Dean G, Moore J, Bradley EC. Low-dose cyclophosphamide and low-dose interleukin-2 for malignant melanoma. Bull N Y Acad Med. 1989;65:128–128. [PMC free article] [PubMed] [Google Scholar]
  • 26.Moore M, Williams DE. Contribution of host immunity to cyclophosphamide therapy of a chemically-induced murine sarcoma. Int J Cancer. 1973;11:358–358. doi: 10.1002/ijc.2910110213. [DOI] [PubMed] [Google Scholar]
  • 27.Morović-Vergles J, Čulo F, Starčević B. The influence of suppressor cells on the antitumor activity of passively transferred immune cells. Period Biol. 1988;88(Suppl 1A):334–334. [Google Scholar]
  • 28.North RJ. Cyclophosphamide adoptive immunotherapy of an established tumor depends on elimination of tumor-induced suppressor T-cells. J Exp Med. 1982;155:1063–1063. doi: 10.1084/jem.155.4.1063. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.North RJ. The murine antitumor immune response and its therapeutic manipulation. A review. Adv Immunol. 1984;35:89–89. doi: 10.1016/s0065-2776(08)60575-1. [DOI] [PubMed] [Google Scholar]
  • 30.Polak L, Rinck C. Effect of elimination of suppressor cells on the development of DNCB contact sensitivity in guinea pigs. Immunology. 1977;33:305–305. [PMC free article] [PubMed] [Google Scholar]
  • 31.Polak L, Turk JL. Reversal of immunological tolerance by cyclophosphamide through inhibition of suppressor cell activity. Nature. 1974;249:654–654. doi: 10.1038/249654a0. [DOI] [PubMed] [Google Scholar]
  • 32.Steele G, Pierce GE. Effects of cyclophosphamide on immunity against chemically-induced syngeneic murine sarcomas. Int J Cancer. 1974;13:572–572. doi: 10.1002/ijc.2910130417. [DOI] [PubMed] [Google Scholar]
  • 33.Tonner E, Sewell HF, Thomson AW. Cancer-induced alterations in T-cell subsets in normal and cyclophosphamide treated mice. Int Arch Appl Immunol. 1988;85:180–180. doi: 10.1159/000234499. [DOI] [PubMed] [Google Scholar]
  • 34.Treves AJ, Cohen IR, Feldman M. A syngeneic metastatic tumor model in mice: the natural immune response of the host and its manipulation. In: Weiss D, editor. Immunological parameters of host tumor relationship, vol. 4. New York: Academic Press; 1976. pp. 89–89. [PubMed] [Google Scholar]
  • 35.Uitdehag BMJ, Nillesen WM, Hommes OR. Long-lasting effects of cyclophosphamide on lymphocytes in peripheral blood and spinal fluid. Acta Neurol Scand. 1989;79:12–12. doi: 10.1111/j.1600-0404.1989.tb03702.x. [DOI] [PubMed] [Google Scholar]
  • 36.Vaage J. Concomitant immunity and specific desensibilization in murine tumor hosts. Israel J Med Sci. 1973;9:332–332. [PubMed] [Google Scholar]
  • 37.Vidović D, Marušić M, Čulo F. Interference of antitumor and immunosuppressive effects of cyclophosphamide in tumor-bearing rats. Analysis of factors determining resistance or susceptibility to a subsequent tumor challenge. Cancer Immunol Immunother. 1982;14:36–36. doi: 10.1007/BF00199430. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Ye QW, Mokyr MB, Pyle JM, Dray S. Suppression of antitumor immunity by macrophages in spleens of mice bearing a large MOPC-315 tumor. Cancer Immunol Immunother. 1984;16:162–162. doi: 10.1007/BF00205423. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Cancer Immunology, Immunotherapy : CII are provided here courtesy of Springer

RESOURCES