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Clinical and Experimental Immunology logoLink to Clinical and Experimental Immunology
. 1993 Oct;94(1):4–10. doi: 10.1111/j.1365-2249.1993.tb05968.x

Peri-operative modulation of cellular immunity in patients with colorectal cancer.

P H Nichols 1, C W Ramsden 1, U Ward 1, L K Trejdosiewicz 1, N S Ambrose 1, J N Primrose 1
PMCID: PMC1534352  PMID: 8403515

Abstract

The peri-operative cellular immune response is depressed in patients with gastrointestinal cancer, a factor which may facilitate malignant dissemination. We have investigated the effects of peri-operative rIL-2 and a combination of rIL-2 and interferon-alpha (IFN-alpha) on both peripheral blood lymphocyte function and number in patients undergoing surgical resection for colorectal cancer. Fifty-two patients were randomly allocated to either control, rIL-2 or rIL-2 with IFN-alpha treatment arms. In vitro studies were performed pre-operatively and on post-operative days 1, 4, 7 and 10. Natural killer (NK) and lymphokine-activated killer (LAK) cell function were profoundly depressed in control patients (P < 0.001; P < 0.01), an effect abrogated in both treatment groups; indeed NK function was augmented in the rIL-2 and IFN-alpha group on the first post-operative day in association with an increase in the percentage of cells expressing CD16 and CD56 (P < 0.01). Flow cytometric analysis of lymphocyte subsets in the control group was unremarkable, except for an early post-operative fall in numbers of lymphocytes. Treatment with either rIL-2 or rIL-2 and IFN-alpha produced an initial profound reduction in T lymphocyte numbers, followed by a 'rebound' lymphocytosis of activated CD3+ T cells, as demonstrated by a significant increase in co-expression of CD25, CD38 and CD45RO. No significant differences were observed between either of the treatment groups. Adjuvant immunotherapy affects peri-operative anti-tumour immune responses, and this may influence long term outcome in patients undergoing surgery for gastrointestinal cancer.

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Selected References

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  1. Atzpodien J., Körfer A., Franks C. R., Poliwoda H., Kirchner H. Home therapy with recombinant interleukin-2 and interferon-alpha 2b in advanced human malignancies. Lancet. 1990 Jun 23;335(8704):1509–1512. doi: 10.1016/0140-6736(90)93039-r. [DOI] [PubMed] [Google Scholar]
  2. Borden E. C., Sondel P. M. Lymphokines and cytokines as cancer treatment. Immunotherapy realized. Cancer. 1990 Feb 1;65(3 Suppl):800–814. doi: 10.1002/1097-0142(19900201)65:3+<800::aid-cncr2820651328>3.0.co;2-y. [DOI] [PubMed] [Google Scholar]
  3. Carlo Stella C., Cazzola M. Interferons as biologic modulators of hematopoietic cell proliferation and differentiation. Haematologica. 1988 May-Jun;73(3):225–237. [PubMed] [Google Scholar]
  4. Dye J. F., Somers S. S., Guillou P. J. Simplified quantitation of cytotoxicity by integration of specific lysis against effector cell concentration at a constant target cell concentration and measuring the area under the curve. J Immunol Methods. 1991 Apr 8;138(1):1–13. doi: 10.1016/0022-1759(91)90058-n. [DOI] [PubMed] [Google Scholar]
  5. Finlay I. G., McArdle C. S. Occult hepatic metastases in colorectal carcinoma. Br J Surg. 1986 Sep;73(9):732–735. doi: 10.1002/bjs.1800730918. [DOI] [PubMed] [Google Scholar]
  6. Gillis S., Ferm M. M., Ou W., Smith K. A. T cell growth factor: parameters of production and a quantitative microassay for activity. J Immunol. 1978 Jun;120(6):2027–2032. [PubMed] [Google Scholar]
  7. Goldstein D., Laszlo J. Interferon therapy in cancer: from imaginon to interferon. Cancer Res. 1986 Sep;46(9):4315–4329. [PubMed] [Google Scholar]
  8. Grimm E. A., Mazumder A., Zhang H. Z., Rosenberg S. A. Lymphokine-activated killer cell phenomenon. Lysis of natural killer-resistant fresh solid tumor cells by interleukin 2-activated autologous human peripheral blood lymphocytes. J Exp Med. 1982 Jun 1;155(6):1823–1841. doi: 10.1084/jem.155.6.1823. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Iigo M., Sakurai M., Tamura T., Saijo N., Hoshi A. In vivo antitumor activity of multiple injections of recombinant interleukin 2, alone and in combination with three different types of recombinant interferon, on various syngeneic murine tumors. Cancer Res. 1988 Jan 15;48(2):260–264. [PubMed] [Google Scholar]
  10. Lennard T. W., Shenton B. K., Borzotta A., Donnelly P. K., White M., Gerrie L. M., Proud G., Taylor R. M. The influence of surgical operations on components of the human immune system. Br J Surg. 1985 Oct;72(10):771–776. doi: 10.1002/bjs.1800721002. [DOI] [PubMed] [Google Scholar]
  11. Lotze M. T., Chang A. E., Seipp C. A., Simpson C., Vetto J. T., Rosenberg S. A. High-dose recombinant interleukin 2 in the treatment of patients with disseminated cancer. Responses, treatment-related morbidity, and histologic findings. JAMA. 1986 Dec 12;256(22):3117–3124. [PubMed] [Google Scholar]
  12. Lundy J., Lovett E. J., 3rd, Hamilton S., Conran P. Halothane, surgery, immunosuppression and artificial pulmonary metastases. Cancer. 1978 Mar;41(3):827–830. doi: 10.1002/1097-0142(197803)41:3<827::aid-cncr2820410307>3.0.co;2-#. [DOI] [PubMed] [Google Scholar]
  13. McMannis J. D., Fisher R. I., Creekmore S. P., Braun D. P., Harris J. E., Ellis T. M. In vivo effects of recombinant IL-2. I. Isolation of circulating Leu-19+ lymphokine-activated killer effector cells from cancer patients receiving recombinant IL-2. J Immunol. 1988 Feb 15;140(4):1335–1340. [PubMed] [Google Scholar]
  14. Moertel C. G., Fleming T. R., Macdonald J. S., Haller D. G., Laurie J. A., Goodman P. J., Ungerleider J. S., Emerson W. A., Tormey D. C., Glick J. H. Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med. 1990 Feb 8;322(6):352–358. doi: 10.1056/NEJM199002083220602. [DOI] [PubMed] [Google Scholar]
  15. Monson J. R., Ramsden C., Guillou P. J. Decreased interleukin-2 production in patients with gastrointestinal cancer. Br J Surg. 1986 Jun;73(6):483–486. doi: 10.1002/bjs.1800730620. [DOI] [PubMed] [Google Scholar]
  16. Nichols P. H., Ramsden C. W., Ward U., Sedman P. C., Primrose J. N. Perioperative immunotherapy with recombinant interleukin 2 in patients undergoing surgery for colorectal cancer. Cancer Res. 1992 Oct 15;52(20):5765–5769. [PubMed] [Google Scholar]
  17. Ortaldo J. R., Bonnard G. D., Herberman R. B. Cytotoxic reactivity of human lymphocytes cultured in vitro. J Immunol. 1977 Oct;119(4):1351–1357. [PubMed] [Google Scholar]
  18. Pescatori M., Mattana C., Maria G., Ferrara A., Lucibello L. Outcome of colorectal cancer. Br J Surg. 1987 May;74(5):370–372. doi: 10.1002/bjs.1800740515. [DOI] [PubMed] [Google Scholar]
  19. Rosenberg S. A., Lotze M. T., Muul L. M., Chang A. E., Avis F. P., Leitman S., Linehan W. M., Robertson C. N., Lee R. E., Rubin J. T. 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. N Engl J Med. 1987 Apr 9;316(15):889–897. doi: 10.1056/NEJM198704093161501. [DOI] [PubMed] [Google Scholar]
  20. Roth J. A., Golub S. H., Grimm E. A., Eilber F. R., Morton D. L. Effects of operation on immune response in cancer patients: sequential evaluation of in vitro lymphocyte function. Surgery. 1976 Jan;79(1):46–51. [PubMed] [Google Scholar]
  21. SALSBURY A. J., MCKINNA J. A., GRIFFITHS J. D., MORGAN C. N. CIRCULATING CANCER CELLS DURING EXCISION OF CARINOMAS OF THE RECTUM AND COLON WITH HIGH LIGATION OF THE INFERIOR MESENTERIC VEIN. Surg Gynecol Obstet. 1965 Jun;120:1266–1270. [PubMed] [Google Scholar]
  22. Sedman P. C., Ramsden C. W., Brennan T. G., Giles G. R., Guillou P. J. Effects of low dose perioperative interferon on the surgically induced suppression of antitumour immune responses. Br J Surg. 1988 Oct;75(10):976–981. doi: 10.1002/bjs.1800751012. [DOI] [PubMed] [Google Scholar]
  23. Slade M. S., Simmons R. L., Yunis E., Greenberg L. J. Immunodepression after major surgery in normal patients. Surgery. 1975 Sep;78(3):363–372. [PubMed] [Google Scholar]
  24. Smith K. A. Interleukin-2: inception, impact, and implications. Science. 1988 May 27;240(4856):1169–1176. doi: 10.1126/science.3131876. [DOI] [PubMed] [Google Scholar]
  25. Sosman J. A., Hank J. A., Sondel P. M. In vivo activation of lymphokine-activated killer activity with interleukin-2: prospects for combination therapies. Semin Oncol. 1990 Feb;17(1 Suppl 1):22–41. [PubMed] [Google Scholar]
  26. Springer T. A. Adhesion receptors of the immune system. Nature. 1990 Aug 2;346(6283):425–434. doi: 10.1038/346425a0. [DOI] [PubMed] [Google Scholar]
  27. Thompson J. A., Lee D. J., Cox W. W., Lindgren C. G., Collins C., Neraas K. A., Dennin R. A., Fefer A. Recombinant interleukin 2 toxicity, pharmacokinetics, and immunomodulatory effects in a phase I trial. Cancer Res. 1987 Aug 1;47(15):4202–4207. [PubMed] [Google Scholar]
  28. Wadler S., Einzig A. I., Dutcher J. P., Ciobanu N., Landau L., Wiernik P. H. Phase II trial of recombinant alpha-2b-interferon and low-dose cyclophosphamide in advanced melanoma and renal cell carcinoma. Am J Clin Oncol. 1988 Feb;11(1):55–59. doi: 10.1097/00000421-198802000-00012. [DOI] [PubMed] [Google Scholar]
  29. Weber J. S., Jay G., Tanaka K., Rosenberg S. A. Immunotherapy of a murine tumor with interleukin 2. Increased sensitivity after MHC class I gene transfection. J Exp Med. 1987 Dec 1;166(6):1716–1733. doi: 10.1084/jem.166.6.1716. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Weese J. L., Ottery F. D., Emoto S. E. Do operations facilitate tumor growth? An experimental model in rats. Surgery. 1986 Aug;100(2):273–277. [PubMed] [Google Scholar]
  31. West W. H., Tauer K. W., Yannelli J. R., Marshall G. D., Orr D. W., Thurman G. B., Oldham R. K. Constant-infusion recombinant interleukin-2 in adoptive immunotherapy of advanced cancer. N Engl J Med. 1987 Apr 9;316(15):898–905. doi: 10.1056/NEJM198704093161502. [DOI] [PubMed] [Google Scholar]
  32. Windle R., Bell P. R., Shaw D. Five year results of a randomized trial of adjuvant 5-fluorouracil and levamisole in colorectal cancer. Br J Surg. 1987 Jul;74(7):569–572. doi: 10.1002/bjs.1800740707. [DOI] [PubMed] [Google Scholar]
  33. Yamashita R., Hiraoka T., Kamimoto I., Miyauchi Y. Prevention of growth of metastases in rat liver by perioperative immunoactivation. Cancer Res. 1986 Jun;46(6):3138–3141. [PubMed] [Google Scholar]

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