Abstract
Although a systemic antitumor immune response by antibodies or T cells is often detected in cancer patients, this response mostly does not result in tumor rejection. The beneficial effect of tumor vaccination on survival rates is limited as tumor response is low. In contrast to solid tumors, circulating tumor cells may be more easily accessible and therefore destroyed by the immune system and thus prevent metastases. This discrepancy is further clarified in our study, by assessing the effect of a systemic immune response on established liver tumors and circulating tumor cells. Male Wag/Rij rats were inoculated with CC531 colorectal tumor cells subcapsulary in the liver, with or without immune suppression (60 mg/kg cyclophosphamide). To study the effect of a systemic immune response, rats received CC531 tumor cells intravenously and three weeks later the number of lung tumors was assessed. Presence of specific anti-CC531 antibodies in serum was determined by flow cytometric analysis at times of inoculation, i.v. tumor cell administration and sacrifice. Rats with liver tumors and subsequent rechallenge produced anti-CC531 IgG antibodies and did not develop lung tumors, whereas without existing liver tumors, rats developed lung tumors upon i.v. administration of CC531 tumor cells. Liver tumors in rats with and without i.v. CC531 tumor cell administration were equal in size. These results showed that a systemic immune response, induced upon liver tumor induction and rechallenge, prevented formation of lung tumors but did not affect tumor growth in the liver. Possibly the immune response lacked the ability to penetrate the protective extracellular matrix surrounding the established liver tumors, which prevented the tumor cells from recognition by and contact with cells of the immune system.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Nagorsen D, Keilholz U, Rivoltini L et al. Natural T-cell response against MHC class I epitopes of epithelial cell adhesion molecule, her-2/neu, and carcinoembryonic antigen in patients with colorectal cancer. Cancer Res 2000; 60(17): 4850–4.
Berd D, Maguire HC Jr, McCue P et al. Treatment of metastatic melanoma with an autologous tumor-cell vaccine: clinical and immunologic results in 64 patients. J Clin Oncol 1990; 8(11): 1858–67.
Harris JE, Ryan L, Hoover HC Jr et al. Adjuvant active specific immunotherapy for stage II and III colon cancer with an autologous tumor cell vaccine: Eastern Cooperative Oncology Group Study E5283. J Clin Oncol 2000;18(1): 148–57.
Hoover HC Jr, Brandhorst JS, Peters LC et al. Adjuvant active specific immunotherapy for human colorectal cancer: 6.5-year median followup of a phase III prospectively randomized trial. J Clin Oncol 1993; 11(3): 390–9.
Gervois N, Guilloux Y, Diez E et al. Suboptimal activation of melanoma infiltrating lymphocytes (TIL) due to low avidity of TCR/MHCtumor peptide interactions. J Exp Med 1996; 183(5): 2403–7.
Kanai T, Watanabe M, Hayashi A et al. Regulatory effect of interleukin-4 and interleukin-13 on colon cancer cell adhesion. Br J Cancer 2000; 82(10): 1717–23.
Gastl GA, Abrams JS, Nanus DM et al.Interleukin-10 production by human carcinoma cell lines and its relationship to interleukin-6 expression. Int J Cancer 1993; 55(1):96–101.
Harding FA, McArthur JG, Gross JA et al. CD28-mediated signalling co-stimulates murine T cells and prevents induction of anergy in T-cell clones. Nature 1992; 356(6370): 607–9.
Inge TH, Hoover SK, Susskind BM et al. Inhibition of tumor-specific cytotoxic T-lymphocyte responses by transforming growth factor beta 1. Cancer Res 1992; 52(6): 1386–92.
Hagenaars M, Ensink NG, Basse PH et al. The microscopic anatomy of experimental rat CC531 colon tumour metastases: consequences for immunotherapy? Clin Exp Metast 2000; 18(2): 189–96.
Kuppen PJ, van der Eb MM, Jonges LE et al. Tumor structure and extracellular matrix as a possible barrier for therapeutic approaches using immune cells or adenoviruses in colorectal cancer. Histochem Cell Biol2001; 115(1):67–72.
Cavallo F, Di Carlo E, Butera M et al. Immune events associated with the cure of established tumors and spontaneous metastases by local and systemic interleukin 12. Cancer Res 1999; 59(2): 414–21.
Pierrefite-Carle V, Baque P, Gavelli A et al. Subcutaneous or intrahepatic injection of suicide gene modified tumour cells induces a systemic antitumour response in a metastatic model of colon carcinoma in rats.Gut 2002; 50(3): 387–91.
Hagenaars M, Zwaveling S, Kuppen PJ et al. Characteristics of tumor infiltration by adoptively transferred and endogenous natural-killer cells in a syngeneic rat model: Implications for the mechanism behind anti-tumor responses. Int J Cancer 1998; 78(6): 783–9.
Rovers JP, Saarnak AE, Molina A et al. Effective treatment of liver metastases with photodynamic therapy, using the second-generation photosensitizer meta-tetra(hydroxyphenyl)chlorin (mTHPC), in a rat model. Br J Cancer1999; 81(4): 600–8.
Wexler H. Accurate identification of experimental pulmonary metastases. J Natl Cancer Inst 1966; 36(4): 641–5.
Mayumi H, Umesue M, Nomoto K. Cyclophosphamide-induced immunological tolerance: An overview. Immunobiology 1996; 195(2): 129–39.
Hoogenhout J, Kazem I, Jerusalem CR et al. Growth pattern of tumor xenografts inWistar rats after treatment with cyclophosphamide, total lymphoid irradiation and/or cyclosporin A. Int J Radiat Oncol Biol Phys 1983; 9(6): 871–9.
Matar P, Rozados VR, Gervasoni SI et al. Th2/Th1 switch induced by a single low dose of cyclophosphamide in a rat metastatic lymphoma model. Cancer Immunol Immunother 2002; 50(11): 588–96.
Rosenberg SA, Lotze MT, Muul LM et al. A progress report on the treatment of 157 patients with advanced cancer using lymphokineactivated killer cells and interleukin-2 or high-dose interleukin-2 alone. N Engl J Med 1987; 316(15): 889–97.
Shimizu K, Fields RC, Giedlin M et al. Systemic administration of interleukin 2 enhances the therapeutic efficacy of dendritic cell-based tumor vaccines. Proc Natl Acad Sci USA 1999; 96(5): 2268–73.
Karpoff HM, D'Angelica M, Blair S et al. Prevention of hepatic tumor metastases in rats with herpes viral vaccines and gamma-interferon. J Clin Invest 1997; 99(4): 799–804.
Chen SH, Pham-Nguyen KB, Martinet O et al. Rejection of disseminated metastases of colon carcinoma by synergism of IL-12 gene therapy and 4-1BB costimulation. Mol Ther 2000; 2(1): 39–46.
Pulaski BA, Clements VK, Pipeling MR et al. Immunotherapy with vaccines combining MHC class II/CD80+ tumor cells with interleukin-12 reduces established metastatic disease and stimulates immune effectors and monokine induced by interferon gamma. Cancer Immunol Immunother2000;49(1):34–45.
Golab J, Stoklosa T, Czajka A et al. Synergistic antitumor effects of a selective proteasome inhibitor and TNF inmice. Anticancer Res 2000; 20(3A): 1717–21.
Zagozdzon R, Stoklosa T, Golab J et al. Augmented antitumor effects of combination therapy with interleukin-12, cisplatin, and tumor necrosis factor-alpha in a murine melanoma model. Anticancer Res1997; 17(6D): 4493–8.
Dabrowska A, Giermasz A, Golab J et al. Potentiated antitumor effects of interleukin 12 and interferon alpha against B16F10 melanoma in mice.Neoplasma 2001; 48(5): 358–61.
Santodonato L, D'Agostino G, Santini SM et al. Local and systemic antitumor response after combined therapy of mouse metastatic tumors with tumor cells expressing IFN-alpha and HSVtk: perspectives for the generation of cancer vaccines. Gene Ther 1997; 4(11): 1246–55.
Odaka M, Sterman DH, Wiewrodt R et al. Eradication of intraperitoneal and distant tumor by adenovirus-mediated interferon-beta gene therapy is attributable to induction of systemic immunity. Cancer Res 2001; 61(16): 6201–12.
Arca MJ, Krauss JC, Aruga A et al. Therapeutic efficacy of T cells derived from lymph nodes draining a poorly immunogenic tumor transduced to secrete granulocyte-macrophage colony-stimulating factor. Cancer Gene Ther 1996; 3(1): 39–47.
Golab J, Zagozdzon R, Stoklosa T et al. Granulocyte colonystimulating factor demonstrates antitumor activity inmelanoma model in mice. Neoplasma 1998; 45(1):35–9.
Perez-Diez A, Spiess PJ, Restifo NP et al. Intensity of the vaccineelicited immune response determines tumor clearance. J Immunol 2002; 168(1): 338–47.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
van Duijnhoven, F.H., Aalbers, R.I., Rothbarth, J. et al. A systemic antitumor immune response prevents outgrowth of lung tumors after i.v. rechallenge but is not able to prevent growth of experimental liver tumors. Clin Exp Metastasis 21, 13–18 (2004). https://doi.org/10.1023/B:CLIN.0000017162.35708.73
Issue Date:
DOI: https://doi.org/10.1023/B:CLIN.0000017162.35708.73