title: Cytokine secretion by genetically modified nonimmunogenic murine fibrosarcoma. Tumor inhibition by IL-2 but not tumor necrosis factor.
abstract: 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.
authors.affiliation: Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: S E
authors.initials: SE
authors.lastname: Karp
authors.forename: A
authors.initials: A
authors.lastname: Farber
authors.forename: J C
authors.initials: JC
authors.lastname: Salo
authors.forename: P
authors.initials: P
authors.lastname: Hwu
authors.forename: G
authors.initials: G
authors.lastname: Jaffe
authors.forename: A L
authors.initials: AL
authors.lastname: Asher
authors.forename: E
authors.initials: E
authors.lastname: Shiloni
authors.forename: N P
authors.initials: NP
authors.lastname: Restifo
authors.forename: J J
authors.initials: JJ
authors.lastname: Mulé
authors.forename: S A
authors.initials: SA
authors.lastname: Rosenberg
mesh_terms: D000818:Animals; D005260:Female; D005354:Fibrosarcoma / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D015870:Gene Expression; D015316:Genetic Therapy; D007376:Interleukin-2 / Q000235:genetics* / Q000378:metabolism; D007694:Killer Cells, Natural / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D014162:Transfection; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000378:metabolism
chemical_list: D007376:Interleukin-2; D014409:Tumor Necrosis Factor-alpha