The Journal of Immunology, Vol 150, Issue 3 896-908, Copyright © 1993 by American Association of Immunologists

ARTICLES

Cytokine secretion by genetically modified nonimmunogenic murine fibrosarcoma. Tumor inhibition by IL-2 but not tumor necrosis factor

SE Karp, A Farber, JC Salo, P Hwu, G Jaffe, AL Asher, E Shiloni, NP Restifo, JJ Mule and SA Rosenberg
Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.

Recent investigations have demonstrated that the in vivo growth of weakly immunogenic murine tumors can be inhibited by genetic manipulations that enable them to secrete a variety of cytokines. Inasmuch as most human tumors fail to elicit a detectable host immune response we questioned whether the growth of a nonimmunogenic murine tumor could be inhibited by the secretion of cytokines. We have thus inserted the cDNA encoding for human IL-2 or TNF into the nonimmunogenic murine fibrosarcoma MCA 102. Tumor cells secreting IL-2 failed to grow in vivo despite normal in vitro growth. This growth inhibition required an intact immune system as tumors grew progressively in mice sublethally irradiated before tumor injection. Tumor inhibition was abrogated by the in vivo depletion, by specific mAb before tumor injection, of either CD8+ T cells or NK cells, but not CD4+ T cells. IL-2 secretion by tumor afforded a significant survival benefit to the animal, and IL-2-secreting tumor limited the growth of admixed nonsecreting parental tumor. Histologic evidence and FACS analyses revealed a dense lymphocytic infiltration of IL-2-secreting tumors composed of both CD4+ and CD8+ T cells. In contrast, secretion of TNF failed to inhibit the growth of MCA 102, and similar lymphocyte subset depletions, or administration of specific anti-TNF mAb had no effect on the growth of TNF secreting MCA 102. In summary, these investigations demonstrated that the host response to this nonimmunogenic tumor can be markedly enhanced by the genetic manipulation of the tumor cells to secrete IL-2, but not TNF. This strategy has potential application for the development of immunotherapies for nonimmunogenic tumors.

This article has been cited by other articles:

				Y. Kimura, H. Mizuno, K. Satake, H. Tahara, and M. Tsukuda Effects of Combined Therapy With Interleukin 2 and Interleukin 12 Gene-Transfected Tumor Vaccine for Head and Neck Carcinoma Arch Otolaryngol Head Neck Surg, November 1, 2003; 129(11): 1181 - 1185. [Abstract] [Full Text] [PDF]

				P. L. Friedlander, C. L. Delaune, J. M. Abadie, M. Toups, J. LaCour, L. Marrero, Q. Zhong, and J. K. Kolls Efficacy of CD40 Ligand Gene Therapy in Malignant Mesothelioma Am. J. Respir. Cell Mol. Biol., September 1, 2003; 29(3): 321 - 330. [Abstract] [Full Text] [PDF]

				M. H. Kershaw, C. Hsu, W. Mondesire, L. L. Parker, G. Wang, W. W. Overwijk, R. Lapointe, J. C. Yang, R.-F. Wang, N. P. Restifo, et al. Immunization against Endogenous Retroviral Tumor-associated Antigens Cancer Res., November 1, 2001; 61(21): 7920 - 7924. [Abstract] [Full Text] [PDF]

				M. R. Graf, R. M. Prins, and R. E. Merchant IL-6 Secretion by a Rat T9 Glioma Clone Induces a Neutrophil-Dependent Antitumor Response with Resultant Cellular, Antiglioma Immunity J. Immunol., January 1, 2001; 166(1): 121 - 129. [Abstract] [Full Text] [PDF]

				A. Schneeberger, F. Koszik, W. Schmidt, R. Kutil, and G. Stingl The Tumorigenicity of IL-2 Gene-Transfected Murine M-3D Melanoma Cells Is Determined by the Magnitude and Quality of the Host Defense Reaction: NK Cells Play a Major Role J. Immunol., June 1, 1999; 162(11): 6650 - 6657. [Abstract] [Full Text] [PDF]

				H. Tanaka, H. Yoshizawa, Y. Yamaguchi, K. Ito, H. Kagamu, E. Suzuki, F. Gejyo, H. Hamada, and M. Arakawa Successful Adoptive Immunotherapy of Murine Poorly Immunogenic Tumor with Specific Effector Cells Generated from Gene-Modified Tumor-Primed Lymph Node Cells J. Immunol., March 15, 1999; 162(6): 3574 - 3582. [Abstract] [Full Text] [PDF]

				K. Shimizu, R. C. Fields, M. Giedlin, and J. J. Mule Systemic administration of interleukin 2 enhances the therapeutic efficacy of dendritic cell-based tumor vaccines PNAS, March 2, 1999; 96(5): 2268 - 2273. [Abstract] [Full Text] [PDF]

				G. Noffz, Z. Qin, M. Kopf, and T. Blankenstein Neutrophils but Not Eosinophils Are Involved in Growth Suppression of IL-4-Secreting Tumors J. Immunol., January 1, 1998; 160(1): 345 - 350. [Abstract] [Full Text] [PDF]