This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Awwad, M. Articles by North, R. J. Search for Related Content PubMed PubMed Citation Articles by Awwad, M. Articles by North, R. J.

Cyclophosphamide-induced Immunologically Mediated Regression of a Cyclophosphamide-resistant Murine Tumor: A Consequence of Eliminating Precursor L3T4⁺ Suppressor T-Cells¹

The Trudeau Institute, Saranac Lake, New York 12983

It was shown that it is possible to use cyclophosphamide (Cy) to cause immunologically mediated regression of the immunogenic, Cy-resistant L5178Y lymphoma in syngeneic and semisyngeneic mice. In order to cause tumor regression it was necessary to give Cy shortly before or shortly after tumor implantation. However, regardless of whether Cy was given before or after tumor implantation, tumor regression did not commence until 10 days of progressive tumor growth, by which time the tumor was 1 cm in diameter. Tumor regression was associated with the presence in the spleen of an increased number of Lyt-2⁺ T-cells capable of passively transferring immunity to tumor-bearing recipients. This augmented level of immunity was sustained throughout the period of tumor regression. In contrast, a lower level of concomitant immunity generated by control tumor bearers decayed after Day 12 of tumor growth. Because the therapeutic effect of Cy could be inhibited by passive transfer of L3T4⁺ T-cells from normal donor mice it is apparent that the therapeutic effect of Cy is based on its ability to preferentially destroy L3T4⁺ suppressor T-cells. These putative precursor suppressor T-cells were regenerated 4 days after being destroyed by Cy. Taken together the results represent a striking example of the negative regulatory influence of suppressor T-cells on the immune response to an immunogenic tumor.

¹ Supported by Grants CA-27794 and CA-16642 from the National Cancer Institute, a grant from RJR Nabisco, and a grant from the Oliver S. and Jennie R. Donaldson Trust.

² To whom requests for reprints should be addressed, at The Trudeau Institute, Immunobiological Research Laboratories, P. O. Box 59, Saranac Lake, NY 12983.

Received 10/ 6/88. Revised 12/22/88. Accepted 1/ 4/89.

This article has been cited by other articles:

				O. J. Finn Cancer Immunology N. Engl. J. Med., June 19, 2008; 358(25): 2704 - 2715. [Full Text] [PDF]

				S. Mittal, N. A. Marshall, L. Duncan, D. J. Culligan, R. N. Barker, and M. A. Vickers Local and systemic induction of CD4+CD25+ regulatory T-cell population by non-Hodgkin lymphoma Blood, June 1, 2008; 111(11): 5359 - 5370. [Abstract] [Full Text] [PDF]

				A. P. Castano, P. Mroz, M. X. Wu, and M. R. Hamblin Photodynamic therapy plus low-dose cyclophosphamide generates antitumor immunity in a mouse model PNAS, April 8, 2008; 105(14): 5495 - 5500. [Abstract] [Full Text] [PDF]

				C. Fonseca and G. Dranoff Capitalizing on the Immunogenicity of Dying Tumor Cells Clin. Cancer Res., March 15, 2008; 14(6): 1603 - 1608. [Abstract] [Full Text] [PDF]

				C. T. Viehl, T. T. Moore, U. K. Liyanage, D. M. Frey, J. P. Ehlers, T. J. Eberlein, P. S. Goedegebuure, and D. C. Linehan Depletion of CD4+CD25+ Regulatory T Cells Promotes a Tumor-Specific Immune Response in Pancreas Cancer-Bearing Mice Ann. Surg. Oncol., September 1, 2006; 13(9): 1252 - 1258. [Abstract] [Full Text] [PDF]

				M. Beyer and J. L. Schultze Regulatory T cells in cancer Blood, August 1, 2006; 108(3): 804 - 811. [Abstract] [Full Text] [PDF]

				J. Taieb, N. Chaput, N. Schartz, S. Roux, S. Novault, C. Menard, F. Ghiringhelli, M. Terme, A. F. Carpentier, G. Darrasse-Jese, et al. Chemoimmunotherapy of tumors: cyclophosphamide synergizes with exosome based vaccines. J. Immunol., March 1, 2006; 176(5): 2722 - 2729. [Abstract] [Full Text] [PDF]

				G. Dranoff The Therapeutic Implications of Intratumoral Regulatory T Cells Clin. Cancer Res., December 1, 2005; 11(23): 8226 - 8229. [Full Text] [PDF]

				M. J. Turk, J. A. Guevara-Patino, G. A. Rizzuto, M. E. Engelhorn, and A. N. Houghton Concomitant Tumor Immunity to a Poorly Immunogenic Melanoma Is Prevented by Regulatory T Cells J. Exp. Med., September 20, 2004; 200(6): 771 - 782. [Abstract] [Full Text] [PDF]

				F. Ichihara, K. Kono, A. Takahashi, H. Kawaida, H. Sugai, and H. Fujii Increased Populations of Regulatory T Cells in Peripheral Blood and Tumor-Infiltrating Lymphocytes in Patients with Gastric and Esophageal Cancers Clin. Cancer Res., October 1, 2003; 9(12): 4404 - 4408. [Abstract] [Full Text] [PDF]

				A. H. Mandpe, K. Tsung, and J. A. Norton Cure of an Established Nonimmunogenic Tumor, SCC VII, With a Novel Interleukin 12-Based Immunotherapy Regimen in C3H Mice Arch Otolaryngol Head Neck Surg, July 1, 2003; 129(7): 786 - 792. [Abstract] [Full Text] [PDF]

				U. K. Liyanage, T. T. Moore, H.-G. Joo, Y. Tanaka, V. Herrmann, G. Doherty, J. A. Drebin, S. M. Strasberg, T. J. Eberlein, P. S. Goedegebuure, et al. Prevalence of Regulatory T Cells Is Increased in Peripheral Blood and Tumor Microenvironment of Patients with Pancreas or Breast Adenocarcinoma J. Immunol., September 1, 2002; 169(5): 2756 - 2761. [Abstract] [Full Text] [PDF]

				V. M. Jovasevic and M. B. Mokyr Melphalan-Induced Expression of IFN-{beta} in MOPC-315 Tumor-Bearing Mice and Its Importance for the Up-Regulation of TNF-{alpha} Expression J. Immunol., November 1, 2001; 167(9): 4895 - 4901. [Abstract] [Full Text] [PDF]

				M. Donepudi, P. Raychaudhuri, J. A. Bluestone, and M. B. Mokyr Mechanism of Melphalan-Induced B7-1 Gene Expression in P815 Tumor Cells J. Immunol., June 1, 2001; 166(11): 6491 - 6499. [Abstract] [Full Text] [PDF]

				D. K. Sojka, M. Donepudi, J. A. Bluestone, and M. B. Mokyr Melphalan and Other Anticancer Modalities Up-Regulate B7-1 Gene Expression in Tumor Cells J. Immunol., June 15, 2000; 164(12): 6230 - 6236. [Abstract] [Full Text] [PDF]

				E. D. Kwon, B. A. Foster, A. A. Hurwitz, C. Madias, J. P. Allison, N. M. Greenberg, and M. B. Burg Elimination of residual metastatic prostate cancer after surgery and adjunctive cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) blockade immunotherapy PNAS, December 21, 1999; 96(26): 15074 - 15079. [Abstract] [Full Text] [PDF]

				K. Staveley-O'Carroll, E. Sotomayor, J. Montgomery, I. Borrello, L. Hwang, S. Fein, D. Pardoll, and H. Levitsky Induction of antigen-specific T cell anergy: An early event in the course of tumor progression PNAS, February 3, 1998; 95(3): 1178 - 1183. [Abstract] [Full Text] [PDF]

				K. Tsung, J. B. Meko, Y. L. Tsung, G. R. Peplinski, and J. A. Norton Immune Response Against Large Tumors Eradicated by Treatment with Cyclophosphamide and IL-12 J. Immunol., February 1, 1998; 160(3): 1369 - 1377. [Abstract] [Full Text] [PDF]