Tumor cells expressing membrane-bound form of IL-4 induce antitumor immunity

Local cytokine concentrations are required for inhibition of tumor growth w ith less toxic side-effects. However, genetically engineered tumor cells se creting cytokines still induce toxicity and activate bystander cells. To ci rcumvent such problems, membrane-bound forms of IL-4 (IL-4m) were expressed on MethA fibrosarcoma tumor cells. Chimeric forms of IL-4 with the type I transmembrane protein CD4 or type II transmembrane protein TNF were designe d to express IL-4 in opposite orientations on the tumor cell surface. The I L-4m on tumor clones was able to support cell growth of the IL-4 dependent cytotoxic cell line (CT.4S) and the Th2 cell clone (D10). Furthermore, the IL-4m tumor clones stimulated proliferation of 2C TCR transgenic spleen cel ls which are responsive to L-d MHC class I molecules. Expression of the IL- 4/TNF chimeric protein on MethA cells elicited antitumor immunity and prote cted from MethA tumor challenge. The proposed tumor vaccine may serve as an effective gene therapy method to avoid the toxicity of recombinant cytokin es and bulk bystander leukocyte stimulation encountered in conventional cyt okine gene therapy.