ANTITUMOR RESPONSE INDEPENDENT OF FUNCTIONAL B-LYMPHOCYTES OR T-LYMPHOCYTES INDUCED BY THE LOCAL AND SUSTAINED-RELEASE OF INTERLEUKIN-2 BY THE TUMOR-CELLS

Transfection of tumor cells with a vector containing the entire coding sequence of human interleukin-2 (hIL-2) was previously shown to conve rt the tumorigenic murine fibrosarcoma line CMS-5 into a non-tumorigen ic line. The failure of the IL-2-secreting tumor to grow in convention al (immunocompetent) mice was attributed to the activation of CD8+ T c ells that exhibited tumor specificity and memory. In order to determin e whether or not the IL-2 produced by the tumor may be activating tumo r cytotoxic effector cells other than B or T cells we have repeated th is study using immunodeficient SCID and SCID-beige mice as syngeneic t umor recipients. In contrast to the rapid growth of the wild-type tumo r, the hIL-2-transfected cells (N2A/IL2/CMS5) did not grow, or grew mo re slowly and regressed, in the mice that lack functional B and T cell s. The inhibition of tumor growth associated with the local release of IL-2 was reversed in mice treated with anti-asialo-GM1 antibodies spe cific for natural killer (NK) lineage cells. In contrast to the studie s with conventional mice, the IL-2-dependent effector cells in the imm unodeficient mice exhibited no evidence of memory. In vitro analysis o f spleen cells from tumor-bearing mice revealed the presence of effect or cells able to lyse YAC-1 target cells as well as the wild-type CMS- 5 and the IL-2-transfected variant tumor lines but unable to lyse P815 cells. The pattern of selective target cell killing and the kinetics of killing were indistinguishable from those observed using tumor necr osis factor alpha (TNFalpha) the mediator associated with natural cyto toxicity cell killing of tumor cells. Histopathology of the IL-2-secre ting tumors in SCID mice reveals the presence of infiltrating lymphoid cells and macrophages that were not observed in the CMS-5 tumors. Con sistent with the notion that the tumor killing in the SCID mice was me diated by TNFalpha, mice bearing IL-2-secreting tumors had elevated le vels of serum TNFalpha and little or no effector cell activity, or TNF alpha was found in tumor-bearing mice treated with anti-asialo-GM1 ant ibody. The results indicate that the cytokine-induced tumor regression observed in the IL-2-transfected tumors is a more complex phenomenon than previously recognized and one that is mediated by effector cells of the NK cell and/or monocyte/macrophage lineages, in addition to CD8 + T cells.